Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1

ABSTRACT

This invention relates to novel compounds of the Formula Ik, Im 1 , Im 2 , Im 5 , In 1 , In 2 , In 5 , lo 1 , lo 2 , lo 5 , Ip 1 , Ip 3 , pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11 β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of Cortisol in a cell or the inhibition of the conversion of cortisone to Cortisol in a cell.

RELATED APPLICATIONS

This application is a U.S. National Stage Entry of InternationalApplication No. PCT/US2010/033157, filed on Apr. 30, 2010. InternationalApplication No. PCT/US2010/033157 claims priority to InternationalApplication No. PCT/US2009/002653, which designated the United Statesand was filed on Apr. 30, 2009. International Application No.PCT/US2010/033157 also claims priority to International Application No.PCT/US2009/004261, which designated the United States and was filed onJul. 23, 2009. The entire teachings of the above applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to inhibitors of 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1), pharmaceutical compositions thereof andmethods of using the same. More particularly, this application isdirected to hydrates of the disclosed inhibitors of 11β-hydroxysteroiddehydrogenase type 1.

BACKGROUND OF THE INVENTION

Glucocorticoids, such as cortisol (hydrocortisone), are steroid hormonesthat regulate fat metabolism, function and distribution, and play a rolein carbohydrate, protein and fat metabolism. Glucocorticoids are alsoknown to have physiological effects on development, neurobiology,inflammation, blood pressure, metabolism, and programmed cell death.Cortisol and other corticosteroids bind both the glucocorticoid receptor(GR) and the mineralocorticoid receptor (MR), which are members of thenuclear hormone receptor superfamily and have been shown to mediatecortisol function in vivo. These receptors directly modulatetranscription via DNA-binding zinc finger domains and transcriptionalactivation domains.

Until recently, the major determinants of glucocorticoid action wereattributed to three primary factors: (1) circulating levels ofglucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal(HPA) axis); (2) protein binding of glucocorticoids in circulation; and(3) intracellular receptor density inside target tissues. Recently, afourth determinant of glucocorticoid function has been identified:tissue-specific pre-receptor metabolism by glucocorticoid-activating and-inactivating enzymes. These 11β-hydroxysteroid dehydrogenase (11β-HSD)pre-receptor control enzymes modulate activation of GR and MR byregulation of glucocorticoid hormones. To date, two distinct isozymes of11-beta-HSD have been cloned and characterized: 11β-HSD1 (also known as11-beta-HSD type 1, 11betaHSD1, HSD11B1, HDL, and HSD11L) and 11β-HSD2.11β-HSD1 is a bi-directional oxidoreductase that regenerates activecortisol from inactive 11-keto forms, whereas 11β-HSD2 is aunidirectional dehydrogenase that inactivates biologically activecortisol by converting it into cortisone.

The two isoforms are expressed in a distinct tissue-specific fashion,consistent with the differences in their physiological roles. 11β-HSD1is widely distributed in rat and human tissues; expression of the enzymeand corresponding mRNA have been detected in human liver, adiposetissue, lung, testis, bone and ciliary epithelium. In adipose tissue,increased cortisol concentrations stimulate adipocyte differentiationand may play a role in promoting visceral obesity. In the eye, 11β-HSD1may regulate intraocular pressure and may contribute to glaucoma; somedata suggest that inhibition of 11β-HSD1 may cause a drop in intraocularpressure in patients with intraocular hypertension (Kotelevstev et al.(1997), Proc. Natl. Acad. Sci. USA 94(26):14924-9). Although 11β-HSD1catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreductionreaction, 11β-HSD1 acts predominantly as a NADPH-dependent oxoreductasein intact cells and tissues, catalyzing the formation of active cortisolfrom inert cortisone (Low et al. (1994) J. Mol. Endocrin. 13: 167-174).In contradistinction, 11β-HSD2 expression is found mainly inmineralocorticoid target tissues such as kidney (cortex and medulla),placenta, sigmoid and rectal colon, salivary gland and colonicepithelial cell lines. 11β-HSD2 acts as an NAD-dependent dehydrogenasecatalyzing the inactivation of cortisol to cortisone (Albiston et al.(1994) Mol. Cell. Endocrin. 105: R11-R17), and has been shown to protectthe MR from glucocorticoid excess (e.g., high levels of receptor-activecortisol) (Blum, et al. (2003) Prog. Nucl. Acid Res. Mol. Biol.75:173-216).

Mutations in either the 11β-HSD1 or the 11β-HSD2 genes result in humanpathology. For example, individuals with mutations in 11β-HSD2 aredeficient in this cortisol-inactivation activity and, as a result,present with a syndrome of apparent mineralocorticoid excess (alsoreferred to as ‘SAME’) characterized by hypertension, hypokalemia, andsodium retention (Edwards et al. (1988) Lancet 2: 986-989; Wilson et al.(1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Similarly, mutations in11β-HSD1 and in the gene encoding a co-localized NADPH-generatingenzyme, hexose 6-phosphate dehydrogenase (H6PD), can result in cortisonereductase deficiency (CRD); these individuals present with ACTH-mediatedandrogen excess (hirsutism, menstrual irregularity, hyperandrogenism), aphenotype resembling polycystic ovary syndrome (PCOS) (Draper et al.(2003) Nat. Genet. 34: 434-439).

Notably, disruption of homeostasis in the HPA axis by either deficientor excess secretion or action results in Cushing's syndrome or Addison'sdisease, respectively (Miller and Chrousos (2001) Endocrinology andMetabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4^(th) Ed.:387-524). Patients with Cushing's syndrome or receiving glucocorticoidtherapy develop reversible visceral fat obesity. The phenotype ofCushing's syndrome patients closely resembles that of Reaven's metabolicsyndrome (also known as Syndrome X or insulin resistance syndrome), thesymptoms of which include visceral obesity, glucose intolerance, insulinresistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven(1993) Ann. Rev. Med. 44: 121-131). Although the role of glucocorticoidsin human obesity is not fully characterized, there is mounting evidencethat 11β-HSD1 activity plays an important role in obesity and metabolicsyndrome (Bujalska et al. (1997) Lancet 349: 1210-1213); (Livingstone etal. (2000) Endocrinology 131: 560-563; Rask et al. (2001) J. Clin.Endocrinol. Metab. 86: 1418-1421; Lindsay et al. (2003) J. Clin.Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J. Clin.Endocrinol. Metab. 88: 3983-3988).

Data from studies in mouse transgenic models supports the hypothesisthat adipocyte 11β-HSD1 activity plays a central role in visceralobesity and metabolic syndrome (Alberts et al. (2002) Diabetologia.45(11): 1526-32). Over-expression in adipose tissue of 11β-HSD1 underthe control of the aP2 promoter in transgenic mice produced a phenotyperemarkably similar to human metabolic syndrome (Masuzaki et al. (2001)Science 294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112:83-90). Moreover, the increased activity of 11β-HSD1 in these mice isvery similar to that observed in human obesity (Rask et al. (2001) J.Clin. Endocrinol. Metab. 86: 1418-1421). In addition, data from studieswith 11β-HSD1-deficient mice produced by homologous recombinationdemonstrate that the loss of 11β-HSD1 leads to an increase in insulinsensitivity and glucose tolerance due to a tissue-specific deficiency inactive glucocorticoid levels (Kotelevstev et al. (1997) Proc. Natl.Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276:41293-41300; Morton et al. (2004) Diabetes 53: 931-938).

The published data supports the hypothesis that increased expression of11β-HSD1 contributes to increased local conversion of cortisone tocortisol in adipose tissue and hence that 11β-HSD1 plays a role in thepathogenesis of central obesity and the appearance of the metabolicsyndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17).Therefore, 11β-HSD1 is a promising pharmaceutical target for thetreatment of the metabolic syndrome (Masuzaki, et al., (2003) Curr. DrugTargets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore,inhibition of 11β-HSD1 activity may prove beneficial in treatingnumerous glucocorticoid-related disorders. For example, 11β-HSD1inhibitors could be effective in combating obesity and/or aspects of themetabolic syndrome cluster, including glucose intolerance, insulinresistance, hyperglycemia, hypertension, and/or hyperlipidemia(Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929;Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al.(2004) Diabetes 53: 931-938). In addition, inhibition of 11β-HSD1activity may have beneficial effects on the pancreas, including theenhancement of glucose-stimulated insulin release (Billaudel and Sutter(1979) Horm. Metab. Res. 11: 555-560; Ogawa et al. (1992) J. Clin.Invest. 90: 497-504; Davani et al. (2000) J. Biol. Chem. 275:34841-34844).

Furthermore, given that inter-individual differences in generalcognitive function have been linked to variability in the long-termexposure to glucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1:69-73) and dysregulation of the HPA axis resulting in chronic exposureto glucocorticoid excess in certain brain subregions has been theorizedto contribute to the decline of cognitive function (McEwen and Sapolsky(1995) Curr. Opin. Neurobiol. 5: 205-216), one might predict thatinhibition of 11β-HSD1 could reduce exposure to glucocorticoids in thebrain and thereby protect against deleterious glucocorticoid effects onneuronal function, including cognitive impairment, dementia, and/ordepression. Notably, it is known that stress and glucocorticoidsinfluence cognitive function (de Quervain et al. (1998) Nature 394:787-790); and it has been shown that 11β-HSD1, through its control ofglucocorticoid action in the brain, may have effects on neurotoxicity(Rajan et al. (1996) Neuroscience 16: 65-70; Seckl (2000)Neuroendocrinol. 18:49-99).

There is also evidence that glucocorticoids and 11β-HSD1 play a role inregulation of in intra-ocular pressure (IOP) (Stokes et al. (2000)Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest.Ophthalmol. Vis. Sci. 42: 2037-2042); if left untreated, elevated IOPcan lead to partial visual field loss and eventually blindness. Thus,inhibition of 11β-HSD1 in the eye could reduce local glucocorticoidconcentrations and IOP, and 11β-HSD1 hence could potentially be used totreat glaucoma and other visual disorders.

Transgenic aP2-11βHSD1 mice exhibit high arterial blood pressure andhave increased sensitivity to dietary salt. Moreover, plasmaangiotensinogen levels are elevated in the transgenic mice, as areangiotensin II and aldosterone; and treatment of the mice with anangiotensin II antagonist alleviates the hypertension (Masuzaki et al.(2003) J. Clinical Invest. 112: 83-90). This suggests that hypertensionmay be caused or exacerbated by 11β-HSD1 activity. Thus, 11β-HSD1inhibitors may be useful for treatment of hypertension andhypertension-related cardiovascular disorders. Inhibition of 11β-HSD1 inmature adipocytes is also expected to attenuate secretion of plasminogenactivator inhibitor 1 (PAI-1), which is an independent cardiovascularrisk factor (Halleux et al. (1999) J. Clin. Endocrinol. Metabl. 84:4097-4105).

Glucocorticoids can have adverse effects on skeletal tissues; andprolonged exposure to even moderate glucocorticoid doses can result inosteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81:3441-3447). In addition, 11β-HSD1 has been shown to be present incultures of human primary osteoblasts as well as cells from adult bone(Cooper et al. (2000) Bone 27: 375-381), and the 11β-HSD1 inhibitorcarbenoxolone has been shown to attenuate the negative effects ofglucocorticoids on bone nodule formation (Bellows et al. (1998) Bone 23:119-125). Thus, inhibition of 11β-HSD1 is predicted to decrease thelocal glucocorticoid concentration within osteoblasts and osteoclasts,thereby producing beneficial effects in various forms of bone disease,including osteoporosis.

11β-HSD1 inhibitors may also be useful for immunomodulation. Althoughglucocorticoids are perceived to suppress the immune system, inactuality, there is a complex, dynamic interaction between the HPA axisand the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl.13: 576-581). Glucocorticoids play a role in modulating the balancebetween cell-mediated and humoral immune response, with highglucocorticoid activity normally associated with a humoral response.Inhibition of 11β-HSD1 therefore can be used a means of shifting theimmune response towards a cell-mediated response. Certain diseasestates, such as tuberculosis, leprosy (Hansen's disease) and psoriasis,trigger immune responses that are biased towards a humoral responsewhereas the more effective immune response may be a cell-mediatedresponse. Hence, 11β-HSD1 inhibitors may be useful for treating suchdiseases.

It has been reported that glucocorticoids inhibit wound healing,especially in diabetic patients with ulcers (Bitar et al. (1999) J.Surg. Res. 82: 234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar(2000) Surgery 127: 687-695; Bitar (1998) Am. J. Pathol. 152: 547-554).Patients that exhibit impaired glucose tolerance and/or type 2 diabetesoften also have impaired wound healing. Glucocorticoids have been shownto increase the risk of infection and delay wound healing (Anstead(1998) Adv. Wound Care 11:277-285). Moreover, there is a correlationbetween elevated levels of cortisol in wound fluid and non-healingwounds (EP Patent App. No. 0 902 288). Recent published patentapplications have suggested that certain 11β-HSD1 inhibitors may beuseful for promoting wound healing (PCT/US2006/043,951).

As evidenced herein, there is a continuing need for new and improveddrugs that inhibit 11β-HSD1. The novel compounds of the instantinvention are effective inhibitors of 11β-HSD1.

SUMMARY OF THE INVENTION

It has now been found that compounds of Formula Im¹ or pharmaceuticallyacceptable salts thereof, are effective inhibitors of 11β-HSD1. Theinvention is a compound represented by Formula (Im¹)

or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

In a first embodiment of the invention, Formula Im¹ and its constituentmembers are defined herein as follows:

R¹ is (a) absent or (b) is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₃)alkoxy(C₁-C₃)alkoxy, or (C₁-C₃)alkoxy(C₁-C₃)alkyland is optionally substituted with up to four groups independentlyselected from fluorine, cyano, oxo, R⁴, R⁴O—, (R⁴)₂N—, R⁴O₂C—, R⁴S,R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—,(R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—,(R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—,R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—,R⁴OS(═O)₂NHC(═O)—, R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—,(R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—,R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—,R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—,(R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—,heterocyclyl, heteroaryl, arylamino and heteroarylamino;

A¹ is (a) a bond, or (b) (C₁-C₃)alkylene, CH₂CH₂O, wherein the oxygen isattached to Cy¹, or CH₂C(═O), wherein the carbonyl carbon is attached toCy¹;

Cy¹ is aryl, heteroaryl, monocyclic cycloalkyl or monocyclicheterocyclyl and is optionally substituted with 1 to 4 groupsindependently selected from fluorine, chlorine, bromine, iodine, cyano,nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkyl-carbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkyl-sulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

The oxodihydropyridyl ring in Formula Im¹ is optionally substituted with1 to 4 groups independently selected from fluorine, chlorine, bromine,iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl,hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl,halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl,(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy,halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy,(C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio,halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio,halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl,(C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl,halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl,halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl,(C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkyl-alkanesulfonyl,halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl,halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonyl-amino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

E is (a) a bond or (b) (C₁-C₃)alkylene or (C₁-C₂)alkylenyloxy, whereinthe O is attached to R², each of which is optionally substituted with 1to 4 groups independently selected from methyl, ethyl, trifluoromethylor oxo;

R² is (C₁-C₆)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and isoptionally substituted with up to 4 groups independently selected fromfluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonyl-amino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

R³ is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₅)cycloalkyl(C₁-C₄)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkoxy, or(C₁-C₃)alkoxy(C₁-C₃)alkyl and is optionally substituted with up to fourgroups independently selected from fluorine, cyano, oxo, R⁴, R⁴O—,(R⁴)₂N—, R⁴O₂C—, R⁴C(═O)O—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—,(R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—,(R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—,(R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—,R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—,R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—,(R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—,R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—,R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—,(R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, spirocycloalkyl;heterocyclyl (which in turn may be optionally substituted with alkyl,haloalkyl, halogen or oxo), heteroaryl (which in turn may be optionallysubstituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl,halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂,N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo),arylamino (which in turn may be optionally substituted with alkyl,alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl,dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amidoand N,N-dialkyl-substituted amido) and heteroarylamino (which in turnmay be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio,alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano,CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substitutedamido, or oxo); and

R⁴ is independently selected from H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl and(C₁-C₆)alkoxy(C₁-C₆)alkyl.

Alternatively, the first embodiment above excludes the compounds ofstructural formulas PR-221 and PR-313, or a pharmaceutically acceptablesalt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a pharmaceutical compositioncomprising i) a pharmaceutically acceptable carrier or diluent, and ii)a compound of Formulas Ik, Im¹, Im², Im⁵, In¹, In², In⁵, lo¹, lo², lo⁵,Ip¹ or Ip³, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.

Another embodiment of the invention is a method of inhibiting 11β-HSD1activity comprising the step of administering to a mammal in need ofsuch treatment an effective amount of a compound of Formulas Ik, Im¹,Im², Im⁵, In¹, In², In⁵, lo¹, lo², lo⁵, Ip¹ or Ip³, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a method of treating a subjectwith a disease associated with the activity or expression of 11β-HSD1,comprising the step of administering to the subject an effective amountof a compound of Formulas Ik, Im¹, Im², Im⁵, In¹, In², In⁵, lo¹, lo²,lo⁵, Ip¹ or Ip³, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.

Another embodiment of the invention is the use of a compound of FormulasIk, Im¹, Im², Im⁵, In¹, In², In⁵, lo¹, lo², lo⁵, Ip¹ or Ip³, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof forthe manufacture of a medicament for inhibiting 11β-HSD1 activity in amammal in need of such treatment.

Another embodiment of the invention is the use of a compound of FormulasIk, Im¹, Im², Im⁵, In¹, In², In⁵, lo¹, lo², lo⁵, Ip¹ or Ip³, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof forthe manufacture of a medicament for treating a subject with a diseaseassociated with the activity or expression of 11β-HSD1.

Another embodiment of the invention is a compound of Formulas Ik, Im¹,Im², Im⁵, In¹, In², In⁵, lo¹, lo², lo⁵, Ip¹ or Ip³, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof foruse in inhibiting 11β-HSD1 activity in a mammal in need of suchtreatment.

Another embodiment of the invention is a compound of Ik, Im¹, Im², Im⁵,In¹, In², In⁵, lo¹, lo², lo⁵, Ip¹ or Ip³, or a pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof for use in fortreating a subject with a disease associated with the activity orexpression of 11β-HSD1.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is the x-ray powder diffraction pattern of the monohydrate ofExample 48.

FIG. 2 is the x-ray powder diffraction pattern of the monohydrate ofExample 75.

DETAILED DESCRIPTION OF THE INVENTION

Another embodiment of the invention is a compound of Formula Ik:

or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof;

R^(1a) is absent or is methyl or ethyl;

Cy² is 2-oxo-1,2-dihydropyridyl optionally substituted by 1 to 4 groupsindependently selected from halo, hydroxy, methoxy, hydroxymethyl,methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,(2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl,methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl,dimethylaminosulfonyl, pyrrolidine-1-sulfonyl,methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl,2-hydroxyethyl and 1-aminoethyl;

R² is phenyl, thienyl, pyridyl or isopropyl each optionally substitutedwith halo, methyl, methylthio or (4-morpholino)methyl; and

R³ is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl eachoptionally substituted with up to two groups independently selected fromMethyl, HO—, MeO—, H₂N—, MeC(═O)NH—, MeS(═O)₂NH—, H₂NC(═O)—, MeNHC(═O)—,HO₂C—, (HO)₂P(═O)O—, H₂NS(═O)₂O—, H₂NS(═O)₂NH—, MeNHC(═O)NH—,MeNHC(═O)O—, oxo, cyano, HO₂C—, HOCH₂CH₂NH—, 4-morpholino,HOCH₂C(═O)NH—, H₂NCH₂C(═O)NH—, EtNHC(═O)NH, MeOC(═O)NH—,MeNHC(═NC≡N)NH—, Me-, MeS-, MeSO₂— MeSO₂N(Me)—MeS(═O)₂NHC(═O)—,imidazolylamino-, imidazolyl, tetrazolyl, H₂NCONH—, H₂NCO₂—, HOCH₂CH₂O—,MeNH—, Me₂N— and MeCONMe.

Another embodiment of the invention is a compound of any one of FormulasIm¹, Im² and Im⁵ or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof:

In Formulas Im¹, Im² and Im⁵, the oxodihydropyridyl ring is optionallysubstituted (substitution at ring carbons bonded to hydrogen and ringnitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a“substitutable ring nitrogen atom”) with up to four substituents asdescribed above. Suitable substituents for the oxodihydropyridyl ringand suitable values for R¹, R², R³, A¹, Cy¹ and E are as defined abovein the first embodiment. Alternatively, suitable substituents for Cy¹and the oxodihydropyridyl ring in Formulas Im¹, Im² and Im⁵ areindependently fluorine, chlorine, bromine, iodine, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; and values for R¹, R², R³,A¹, Cy¹ and E are as defined above in the first embodiment.Alternatively, suitable substituents for Cy¹ include (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, cyano andnitro; suitable substituents for a substitutable ring nitrogen atom inthe oxodihydropyridyl ring in Formulas Im¹, Im² and Im⁵ include(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, and(C₁-C₄)haloalkyl; suitable substituents for a ring carbon atom in theoxodihydropyridyl ring in Formulas Im¹, Im² and Im⁵ include fluorine,chlorine, cyano, hydroxy, amino, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl and (C₁-C₄)alkylcarbonylamino; and suitablevalues for R¹, R², R³, A¹, Cy¹ and E are as defined above in the firstembodiment. In another alternative, the embodiments in this paragraphexclude the following compounds:

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

and

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

For each of the embodiments described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Im¹, Im² and Im⁵, R¹ is preferably methyl or ethyl;and R³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Im¹, Im² and Im⁵, R¹ is preferably methyl or ethyl;and R³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Im¹, Im² and Im⁵, R¹ is preferably methyl or ethyl;R² is phenyl optionally substituted with 1, 2 or 3 substituents selectedfrom halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, and SO₂Me; andR³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Im¹, Im² and Im⁵, R¹ is preferably methyl or ethyl;R² is phenyl optionally substituted with 1, 2 or 3 substituents selectedfrom halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, and SO₂Me; andR³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropylor 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Im¹, Im² and Im⁵, R¹ is preferably methyl or ethyl;and R³ is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Im¹, Im² and Im⁵, R¹ is preferably methyl or ethyl;R² is phenyl or fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Im¹, Im² and Im⁵, R¹ is preferably methyl or ethyl;R² is phenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; the substituent on the substitutable ringnitrogen atom in the oxodihydropyridyl ring in Formulas Im¹, Im² and Im⁵is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, or(C₁-C₂)haloalkyl; and one or two ring carbon atoms in theoxodihydropyridyl ring in Formulas Im¹, Im² and Im⁵ are optionallysubstituted with methyl or ethyl.

Another embodiment of the invention is a compound of any one of FormulasIn¹, In² and In⁵, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof:

In Formulas In¹, In² and In⁵, the oxodihydropyridyl ring is optionallysubstituted (substitution at ring carbons bonded to hydrogen and atnitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a“substitutable ring nitrogen atom”) with up to four substituents asdescribed above for Cy². Suitable substituents for the oxodihydropyridylring and suitable values for R¹, R², R³ and Cy¹ are as defined above inthe first embodiment. Alternatively, suitable substituents for Cy¹ andthe oxodihydropyridyl ring in Formulas In¹, In² and In⁵ areindependently fluorine, chlorine, bromine, iodine, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkyl-alkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; and values for R¹, R², R³and Cy¹ are as defined above in the first embodiment. Alternatively,suitable substituents for Cy¹ include (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen, cyano and nitro; suitablesubstituents for a substitutable ring nitrogen atom in theoxodihydropyridyl ring in Formulas In¹, In² and In⁵ include(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl and(C₁-C₄)haloalkyl; suitable substituents for a ring carbon atom in theoxodihydropyridyl ring in Formulas In¹, In² and In⁵ include fluorine,chlorine, cyano, hydroxy, amino, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl and (C₁-C₄)alkylcarbonylamino; and suitablevalues for R¹, R², R³, and Cy¹ are as defined above in the firstembodiment. In another alternative, the embodiments described in thisparagraph exclude the compounds PR-221 and PR-313; or a pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

For each of the embodiments described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas In¹, In² and In⁵, R¹ is preferably methyl or ethyl;and R³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas In¹, In² and In⁵, R¹ is preferably methyl or ethyl;and R³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas In¹, In² and In⁵, R¹ is preferably methyl or ethyl;R² is phenyl optionally substituted with 1, 2 or 3 substituents selectedfrom halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; andR³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas In¹, In² and In⁵, R¹ is preferably methyl or ethyl;R² is phenyl optionally substituted with 1, 2 or 3 substituents selectedfrom halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; andR³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropylor 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas In¹, In² and In⁵, R¹ is preferably methyl or ethyl;and R³ is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas In¹, In² and In⁵, R¹ is preferably methyl or ethyl;R² is phenyl or fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas In¹, In² and In⁵, R¹ is preferably methyl or ethyl;R² is phenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; the substituent on the substitutable ringnitrogen atom in the oxodihydropyridyl rings in Formulas In¹, In² andIn⁵ is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl,or (C₁-C₂)haloalkyl; and one or two ring carbon atoms in theoxodihydropyridyl rings in Formulas In¹, In² and In⁵ are optionallysubstituted with methyl or ethyl.

Another embodiment of the invention is a compound of any one of Formulaslo¹, lo² and lo⁵, or a pharmaceutically acceptable salt thereof:

In Formulas lo¹, lo² and lo⁵, the oxodihydropyridyl ring in Formulaslo¹, lo² and lo⁵ is optionally substituted (substitution at ring carbonsbonded to hydrogen and at nitrogen atoms bonded to hydrogen atoms areencompassed, i.e., a “substitutable ring nitrogen atom”) with up to foursubstituents as described above in the first embodiment; suitable valuesfor G¹ are fluorine, chlorine, bromine, iodine, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; n is 0, 1, 2 or 3; andsuitable substituents for the oxodihydropyridyl ring and suitable valuesfor R¹, R² and R³ are as defined above in the first embodiment.Alternatively, n is 0, 1, 2 or 3; suitable values for G¹ andsubstituents for the oxodihydropyridyl ring in Formulas lo¹, lo² and lo⁵are independently fluorine, chlorine, bromine, iodine, cyano, nitro,amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkyl-alkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and(C₁-C₆)alkylcarbonyl; and values for R¹, R² and R³ are as defined abovein the first embodiment. Alternatively, n is 0, 1, 2 or 3; suitablevalues for G¹ include (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, cyano and nitro; suitable substituents for asubstitutable ring nitrogen atom in the oxodihydropyridyl ring inFormulas lo¹, lo² and lo⁵ include C₁-C₄ alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl and C₁-C₄ haloalkyl; suitable substituentsfor a ring carbon atom in the oxodihydropyridyl ring in Formulas lo¹,lo² and lo⁵ include fluorine, chlorine, cyano, hydroxy, amino,(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, CONH₂,(C₁-C₄)alkylaminocarbonyl, di(C₁-C₄)alkylaminocarbonyl and(C₁-C₄)alkylcarbonylamino; and suitable values for R¹, R² and R³ are asdefined above in the first embodiment. In another alternative, theembodiments described in this paragraph exclude the compounds PR-221 andPR-313; or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.

For each of the embodiments described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas lo¹, lo² and lo⁵, R¹ is preferably methyl or ethyl;and R³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas lo¹, lo² and lo⁵, R¹ is preferably methyl or ethyl;and R³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas lo¹, lo² and lo⁵, R¹ is preferably methyl or ethyl;R² is phenyl optionally substituted with 1, 2 or 3 substituents selectedfrom halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; andR³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas lo¹, lo² and lo⁵, R¹ is preferably methyl or ethyl;R² is phenyl optionally substituted with 1, 2 or 3 substituents selectedfrom halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; andR³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropylor 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas lo¹, lo² and lo⁵, R¹ is preferably methyl or ethyl;and R³ is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas lo¹, lo² and lo⁵, R¹ is preferably methyl or ethyl;R² is phenyl or fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas lo¹, lo² and lo⁵, R¹ is preferably methyl or ethyl;R² is phenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; the substituent on the substitutable ringnitrogen atom in the oxodihydropyridyl ring in Formulas lo¹, lo² and lo⁵is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, or(C₁-C₂)haloalkyl; and one or two ring carbon atoms in theoxodihydropyridyl rings in Formulas lo¹, lo² and lo⁵ are optionallysubstituted with methyl or ethyl.

Another embodiment of the invention (referred to herein as the “FirstAlternate Embodiment”) is a compound represented by Structural Formulaslo¹, lo² and lo⁵, wherein: n is 0 or 1, preferably 0; each G¹ isindependently (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, cyano or nitro; the oxodihydropyridyl issubstituted at its ring nitrogen atom with hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl ordi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; the oxodihydropyridyl isoptionally substituted at one or more substitutable ring carbon atomswith a group independently selected from fluorine, chlorine, cyano,hydroxy, amino, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl and (C₁-C₄)alkylcarbonylamino; R¹ is methylor ethyl; R² is phenyl, thienyl, pyridyl or isopropyl each optionallysubstituted with up to three groups independently selected from halo,methyl, methylthio, (4-morpholino)methyl or cyclopropyl; and R³ ismethyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl eachoptionally substituted with up to two groups independently selected frommethyl, HO—, MeO—, H₂N—, MeC(═O)NH—, MeS(═O)₂NH—, H₂NC(═O)—, MeNHC(═O)—,HO₂C—, (HO)₂P(═O)O—, H₂NS(═O)₂O—, H₂NS(═O)₂NH—, MeNHC(═O)NH—,MeNHC(═O)O—, oxo, cyano, HO₂C—, HOCH₂CH₂NH—, 4-morpholino,HOCH₂C(═O)NH—, H₂NCH₂C(═O)NH—, EtNHC(═O)NH, MeOC(═O)NH—,MeNHC(═NC≡N)NH—, Me-, MeS-, MeSO₂— MeSO₂N(Me)—, MeS(═O)₂NHC(═O)—,imidazolylamino-, imidazolyl, tetrazolyl, H₂NCONH—, H₂NCO₂—, HOCH₂CH₂O—,MeNH—, Me₂N— and MeCONMe.

Alternatively for Structural Formulas lo¹, lo² and lo⁵, R² is phenyloptionally substituted with 1, 2 or 3 substituents independentlyselected from halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl andSO₂Me; and R³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described above for the First Alternate Embodiment.

Alternatively for Structural Formulas lo¹, lo² and lo⁵, R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed above for the First Alternate Embodiment.

Alternatively for Structural Formulas lo¹, lo² and lo⁵, R² is phenyloptionally substituted with 1, 2 or 3 substituents independentlyselected from halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl andSO₂Me; and R³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described in the First Alternate Embodiment.

Alternatively for Structural Formulas lo¹, lo² and lo⁵, R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described in the First Alternate Embodiment.

Alternatively for Structural Formulas lo¹, lo² and lo⁵, R² is phenyl orfluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed in the First Alternate Embodiment.

Alternatively for Structural Formulas lo¹, lo² and lo⁵, R² is phenyl orfluorophenyl; R³ is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;one or two ring carbon atoms in the oxodihydropyridyl rings areoptionally substituted with fluorine, methyl or ethyl; and the remainderof the variables are as described in the First Alternate Embodiment.

For the embodiment described in the previous seven paragraphs, n is 0and all of the substitutable ring carbons in the oxodihydropyridyl arepreferably unsubstituted.

Another embodiment of the invention is a compound represented by any oneof Formulas Ip¹ and Ip³, or a pharmaceutically acceptable salt thereof:

In Formulas Ip¹ and Ip³, G¹ is (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen, cyano or nitro; n is 0, 1or 2; G^(2a) is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl or (C₁-C₄)haloalkyl; G^(2b) is hydrogen,fluorine, chlorine, cyano, hydroxy, amino, (C₁-C₄)alkyl,(C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl or (C₁-C₄)alkylcarbonylamino; and suitablevalues for R¹, R² and R³ are as defined above in the first embodiment.In another alternative, the embodiments described in this paragraphexclude the compounds PR-221 and PR-313; or a pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

For each of the embodiments described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; and R³is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; and R³is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; and R³is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; the substituent G^(2a) is selected from(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, and(C₁-C₂)haloalkyl; and G^(2b) is optionally selected from hydrogen,methyl or ethyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; the substituent G^(2a) is selected fromhaloalkyl, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, and (C₁-C₂)haloalkyl; and G^(2b) isoptionally selected from hydrogen, methyl or ethyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ip¹ and Ip³, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; the substituent G^(2a) is selected fromdifluoromethyl, ethyl substituted with one to three fluorine(preferably, 2-fluoroethyl or 2,2,2-fluoroethyl), (C₁-C₄)alkyl,(C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, and (C₁-C₂)haloalkyl;and G^(2b) is optionally selected from hydrogen, methyl or ethyl.Another embodiment of the invention (referred to herein as the “SecondAlternate Embodiment”) is a compound represented by Structural FormulasIp¹ and Ip³, wherein: n is 0 or 1, preferably 0; each G¹ isindependently (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, cyano or nitro; G^(2a) ishydroxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-carbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl ordi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; G^(2b) is hydrogen,fluorine, chlorine, cyano, hydroxy, amino, (C₁-C₄)alkyl,(C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl or (C₁-C₄)alkylcarbonylamino; R¹ is methylor ethyl; R² is phenyl, thienyl, pyridyl or isopropyl each optionallysubstituted with up to three groups independently selected from halo,methyl, methylthio or (4-morpholino)methyl; and R³ is methyl, ethyl,propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substitutedwith up to two groups independently selected from methyl, HO—, MeO—,H₂N—, MeC(═O)NH—, MeS(═O)₂NH—, H₂NC(═O)—, MeNHC(═O)—, HO₂C—,(HO)₂P(═O)O—, H₂NS(═O)₂O—, H₂NS(═O)₂NH—, MeNHC(═O)NH—, MeNHC(═O)O—, oxo,cyano, HO₂C—, HOCH₂CH₂NH—, 4-morpholino, HOCH₂C(═O)NH—, H₂NCH₂C(═O)NH—,EtNHC(═O)NH, MeOC(═O)NH—, MeNHC(═NC≡N)NH—, Me-, MeS-, MeSO₂—MeSO₂N(Me)—,MeS(═O)₂NHC(═O)—, imidazolylamino-, imidazolyl, tetrazolyl, H₂NCONH—,H₂NCO₂—, HOCH₂CH₂O—, MeNH—, Me₂N— and MeCONMe.

Alternatively for Structural Formulas Ip¹ and Ip³, R² is phenyloptionally substituted with 1, 2 or 3 substituents independentlyselected from halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl andSO₂Me; and R³ is MeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂,3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described above for the Second AlternateEmbodiment.

Alternatively for Structural Formulas Ip¹ and Ip³, R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed above for the Second Alternate Embodiment.

Alternatively for Structural Formulas Ip¹ and Ip³, R² is phenyloptionally substituted with 1, 2 or 3 substituents independentlyselected from halo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl andSO₂Me; and R³ is H₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described in the Second Alternate Embodiment.

Alternatively for Structural Formulas Ip¹ and Ip³, R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described in the Second Alternate Embodiment.

Alternatively for Structural Formulas Ip¹ and Ip³, R² is phenyl orfluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed in the Second Alternate Embodiment.

Alternatively for Structural Formulas Ip¹ and Ip³, R² is phenyl orfluorophenyl; R³ is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;one or two substitutable ring carbon atoms in the oxodihydropyridylrings are optionally substituted with fluorine, methyl or ethyl; and theremainder of the variables are as described in the Second AlternateEmbodiment.

For the embodiment described in the previous seven paragraphs, n is 0and G^(2b) is preferably —H.

Another embodiment of the invention is a hydrate or monohydrate of(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-oneand pharmaceutically acceptable salts thereof. Both, neutral and saltforms of the hydrate and monohydrate are also included. Preferably, thesalt form is pharmaceutically acceptable.

Compounds of the invention are also disclosed in INHIBITORS OF11β-HYDROXYSTEROID DEHYDOGENASE I, U.S. Provisional Application No.61/135,933, filed Jul. 25, 2008; Cyclic Inhibitors Of 11β-HydroxysteroidDehydrogenase 1, U.S. Provisional Application No. 61/135,933, filed May1, 2008; Cyclic Inhibitors Of 11β-Hydroxysteroid Dehydrogenase 1, U.S.Provisional Application No. 61/137,148, filed Jul. 25, 2008; and CyclicInhibitors Of 11β-hydroxysteroid Dehydrogenase 1, InternationalApplication No. PCT/US2008/009017, filed Jul. 25, 2008; the entireteachings of these applications are incorporated herein by reference intheir entirety.

Definitions

The term “alkyl” means a straight or branched hydrocarbon radical having1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term “cycloalkyl” means a monocyclic, bicyclic or tricyclic,saturated hydrocarbon ring having 3-10 carbon atoms and includes, forexample, cyclopropyl (c-Pr), cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl,spiro[4.4]nonane, adamantyl and the like.

The term “aryl” means an aromatic radical which is a phenyl group, anaphthyl group, an indanyl group or a tetrahydronaphthalene group. Anaryl group is optionally substituted with 1-4 substituents. Exemplarysubstituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen,trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂,N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.

The term “heteroaryl” means a 5- and 6-membered heteroaromatic radicalwhich may optionally be fused to a saturated or unsaturated ringcontaining 0-4 heteroatoms selected from N, O, and S and includes, forexample, a heteroaromatic radical which is 2- or 3-thienyl, 2- or3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-,or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl,1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-,6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-,4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-, or5-imidazolyl. A heteroaryl is optionally substituted. Exemplarysubstituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen,trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂,N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or byoxo to form an N-oxide.

The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated orpartially unsaturated heterocyclic ring containing 1 to 4 heteroatomsindependently selected from N, O, and S. Exemplary heterocyclyls includepyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine,piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine,1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine,1,4-dihydro-4-oxopyridine, piperazin-2-one,3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine,tetrahydrofuran, tetrahydropyran, tetrahydrothiophene,tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane,1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one,imidazolidin-2-one, imidazolidine-2,4-dione,tetrahydropyrimidin-2(1H)-one, morpholine, N-methylmorpholine,morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine1,1-dioxide, tetrahydro-1,2,5-thiaoxazole 1,1-dioxide,tetrahydro-2H-1,2-thiazine 1,1-dioxide, hexahydro-1,2,6-thiadiazine1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide isothiazolidine1,1-dioxide, 6-oxo-1,6-dihydropyridazin-3-yl,6-oxo-1,6-dihydropyridazin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yland 5-oxo-4,5-dihydro-1H-imidazol-2-yl. A heterocyclyl can be optionallysubstituted with 1-4 substituents. Exemplary substituents include alkyl,haloalkyl, halogen and oxo.

The term “spirocycloalkyl” means a cycloalkyl group which shares onering carbon with another alkyl or cycloalkyl group.

As used herein the terms “subject” and “patient” may be usedinterchangeably, and means a mammal in need of treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals (e.g.,cows, pigs, horses, sheep, goats and the like) and laboratory animals(e.g., rats, mice, guinea pigs and the like). Typically, the subject isa human in need of treatment.

When a disclosed compound or its pharmaceutically acceptable salt isnamed or depicted by structure, it is to be understood that solvates orhydrates of the compound or its pharmaceutically acceptable salts arealso included. “Solvates” refer to crystalline forms wherein solventmolecules are incorporated into the crystal lattice duringcrystallization. Solvate may include water or nonaqueous solvents suchas ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.Solvates, wherein water is the solvent molecule incorporated into thecrystal lattice, are typically referred to as “hydrates.” Hydratesinclude stoichiometric hydrates as well as compositions containingvariable amounts of water. Some of the compounds disclosed in theexemplification may be in the anhydrous form.

The term “compound” also includes labeling at one or more positions withdeuterium. “Labeled with deuterium at a position” means that the amountdeuterium at the position is greater than the amount that is present atnatural abundance. In certain instances, the deuterium at each positionin a “compound” is at natural abundance.

Certain of the disclosed compounds may exist in various stereoisomericforms. Stereoisomers are compounds that differ only in their spatialarrangement. Enantiomers are pairs of stereoisomers whose mirror imagesare not superimposable, most commonly because they contain anasymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat are not related as mirror images, most commonly because theycontain two or more asymmetrically substituted carbon atoms. The symbol“*” in a structural formula represents the presence of a chiral carboncenter. “R” and “S” represent the configuration of substituents aroundone or more chiral carbon atoms. Thus, “R*” and “S*” denote the relativeconfigurations of substituents around one or more chiral carbon atoms.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity;i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration.

“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicateconfigurations relative to the core molecule.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight pure relative to the other stereoisomers.When a single enantiomer is named or depicted by structure, the depictedor named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight optically pure. Percent optical purity by weight is the ratio ofthe weight of the enantiomer over the weight of the enantiomer plus theweight of its optical isomer.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry, and the compound has at least one chiralcenter, it is to be understood that the name or structure encompassesone enantiomer of compound free from the corresponding optical isomer, aracemic mixture of the compound and mixtures enriched in one enantiomerrelative to its corresponding optical isomer.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry and has at least two chiral centers, itis to be understood that the name or structure encompasses adiastereomer free of other diastereomers, a pair of diastereomers freefrom other diastereomeric pairs, mixtures of diastereomers, mixtures ofdiastereomeric pairs, mixtures of diastereomers in which onediastereomer is enriched relative to the other diastereomer(s) andmixtures of diastereomeric pairs in which one diastereomeric pair isenriched relative to the other diastereomeric pair(s).

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to non-toxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable basic/cationic salts include, the sodium,potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine,L-lysine, L-arginine, ammonium, ethanolamine, piperazine andtriethanolamine salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, malonate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate,phosphate/diphospate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate,teoclate, tosylate, and triethiodide salts.

The following abbreviations have the indicated meanings:

Abbreviation Meaning A % Area percentage Boc tert-butoxy carbonyl ort-butoxy carbonyl (Boc)₂O di-tert-butyl dicarbonate CbzBenzyloxycarbonyl CbzCl Benzyl chloroformate c-Pr cyclopropyl DASTdiethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCC N,N′-dicyclohexylcarbodiimide DCU N,N′-dicyclohexylurea DIADdiisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DIEAN,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMFN,N-dimethylformamide DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2,4-DNP2,4-dinitrophenylhydrazine dppf 1,1′-Bis(diphenylphosphino)ferroceneDPTBS Diphenyl-t-butylsilyl dr diastereomer ratio EDC•HCl, EDCl1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride Equivequivalents EtOAc Ethyl acetate Fmoc1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- Fmoc-OSu1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- pyrrolidinedione h, hrhour(s) HOBt 1-hydroxybenzotriazole HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HBTU2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateKHMDS potassium hexamethyldisilazane LAH or LiAlH₄ lithium aluminumhydride LC-MS liquid chromatography-mass spectroscopy LHMDS lithiumhexamethyldisilazane m-CPBA meta-chloroperoxybenzoic acid Me methyl MsClmethanesulfonyl chloride Min minute MS mass spectrum MTBE, TBME Methylt-butyl ether NaH sodium hydride NaHCO₃ sodium bicarbonate NaN₃ sodiumazide NaOH sodium hydroxide Na₂SO₄ sodium sulfate NMM N-methylmorpholineNMP N-methylpyrrolidinone Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether Quantquantitative yield rt room temperature Satd saturated SOCl₂ thionylchloride SFC supercritical fluid chromatography SPA scintillationproximity assay SPE solid phase extraction TBAF tetrabutylammoniumfluoride TBS t-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TBSClt-butyldimethylsilyl chloride TBDPSCl t-butyldiphenylsilyl chloride TEAtriethylamine or Et₃N TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy freeradical Teoc 1-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5- dione T_(ext)External temperature T_(int) Internal temperature TFA trifluoroaceticacid Tlc, TLC thin layer chromatography TMS trimethylsilyl TMSClchlorotrimethylsilane or trimethylsilyl chloride t_(R) retention timeTsOH p-toluenesulfonic acid

General Description of Synthetic Methods

Compounds of Formula I* can be prepared by several processes. In thediscussion below, A¹, Cy¹, E, R¹, R², R³, Y and n have the meaningsindicated above unless otherwise noted. Cy² is an optionally substituted2-oxo-1,2-dihydropyridyl group. In cases where the syntheticintermediates and final products of Formula I* described below containpotentially reactive functional groups, for example amino, hydroxyl,thiol and carboxylic acid groups, that may interfere with the desiredreaction, it may be advantageous to employ protected forms of theintermediate. Methods for the selection, introduction and subsequentremoval of protecting groups are well known to those skilled in the art.(T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis”John Wiley & Sons, Inc., New York 1999). Such protecting groupmanipulations are assumed in the discussion below and not describedexplicitly. Generally, reagents in the reaction schemes are used inequimolar amounts; however, in certain cases it may be desirable to usean excess of one reagent to drive a reaction to completion. This isespecially the case when the excess reagent can be readily removed byevaporation or extraction. Bases employed to neutralize HCl in reactionmixtures are generally used in slight to substantial excess (1.05-5equivalents).

In a first process a compound of Formula I*, can be prepared by reactionof an aminoalcohol intermediate of Formula II with a reagent of FormulaIII, wherein Z¹ and Z² are leaving groups such as chloride, 1-imidazolylor aryloxide in an inert solvent such as THF, CH₂Cl₂, toluene or MeCN,usually in the presence of an organic or inorganic base such astriethylamine or NaHCO₃ respectively, at −10° C. to 120° C.:

Certain instances of reagent III are especially convenient because theyare commercially available. For example when Z¹ and Z² are bothchloride, III is phosgene. When Z¹ and Z² are both 1-imidazolyl, III iscarbonyl diimidazole. When Z¹ is chloride and Z² is p-nitrophenoxide,III is p-nitrophenyl chloroformate. When Z¹ and Z² are both OCCl₃, IIIis triphosgene and as little as one third of molar equivalent can beused.

Aminoalcohol intermediates of Formula II can be prepared by reduction ofamides of Formula IV using a hydride reagent such as BH₃.THF solution,BH₃.Me₂S or LiAlH₄ in an inert solvent ethereal such as THF or DME at20° C. to 100° C. for between 1 h and 48 h:

Intermediates of Formula IV can be prepared by coupling of aβ-hydroxyacid of Formula V with an amine of Formula VI using standardpeptide coupling reagents such as EDC in the presence of HOBt andN,N-diisopropylethylamine in an inert solvent such as CH₂Cl₂ at 0-30° C.for between 1 h and 24 h:

Amine intermediates of Formula VI, wherein A¹=CH₂ and R¹ is absent, canbe prepared by reduction of amides of Formula VII using a hydridereagent such as BH₃.THF solution, BH₃.Me₂S or LiAlH₄ in an inert solventethereal such as THF or DME at 20° C. to 100° C. for between 1 h and 48h:

Amine intermediates of Formula VI, wherein A¹ is a bond, R¹ is absentand Cy¹ is not an aromatic or heteroaromatic ring, can be prepared fromketones of formula VIII via oximes of Formula IX or by reductiveamination of a ketone of Formula VIII with ammonia:

Methods for the conversion of ketones to oximes are described in Smith,M. B. and March, J. “March's Advanced Organic Chemistry” pp 1194-1195,5^(th) Edition, Wiley, New York, N.Y., 2001. Methods for the reductionof oximes to primary amines are described in Smith, M. B. and March, J.“March's Advanced Organic Chemistry” p 1555, 5^(th) Edition, Wiley, NewYork, N.Y., 2001. Methods for the reductive amination of ketones aredescribed in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume59, Ed. Overman, L. E., Wiley Interscience, 2002.

Similarly amine intermediates of Formula VI, wherein A¹ is CH and R¹ ismethyl or ethyl, can be prepared by reduction t-butylsulfinylimines ofFormula VIIIb which can be prepared from ketones of Formula VIIIa andt-butylsulfinamide or by addition of organometallic reagents of FormulaR¹M, wherein R1 is Me or Et and M is Li, MgCl, MgBr or MgI, tot-butylsulfinylimines of Formula VIIId which can be prepared fromaldehydes of Formula VIIIc.

High stereoselectivity is often achieved in such reactions using chiralt-butylsulfinylimines.

Intermediates of Formula II, wherein n=0, can be prepared by reaction ofoxetanes of Formula X with amines of Formula VI as described in Smith,M. B. and March, J. “March's Advanced Organic Chemistry” p 505, 5^(th)Edition, Wiley, New York, N.Y., 2001:

Intermediates of Formula II can also be prepared by reductive aminationof β-hydroxyaldehydes of Formula Xa with amines of Formula VI. Methodsfor the reductive amination of aldehydes are described in Baxter, E. W.and Reitz, A. B. “Organic Reactions” Volume 59, Ed. Overman, L. E.,Wiley Interscience, 2002.

Aldehydes of Formula Xa can be prepared from homoallylic alcohols ofFormula XXI by treatment with OsO₄ and NaIO₄.

Intermediates of Formula II, wherein A¹=CH₂ and R¹ is absent, can beprepared by reduction of amide intermediates of formula XI using ahydride reagent such as BH₃.THF solution, BH₃.Me₂S or LiAlH₄ in an inertsolvent ethereal such as THF or DME at 20° C. to 100° C. for between 1 hand 48 h:

Amide intermediates of Formula XI can be prepared by reaction of anamino-alcohol intermediate of Formula XII with activated carboxylic acidof Formula XIII wherein Z³=chloride or an activated ester, such as anN-hydroxysuccinimide ester:

Amino-alcohol intermediates of Formula XII, wherein n=0, can be preparedby reaction of an epoxide of Formula XIV with cyanide ion followed byreduction of the resulting hydroxynitrile of Formula XV with hydrogengas in the presence of a catalyst or with a hydride source such asLiAlH₄:

Epoxide compounds of formula XIV can, in turn, be prepared in a numberof ways including, as described in Aube, J. “Epoxidation and RelatedProcesses” Chapter 3.2 in Volume 1 of “Comprehensive Organic Synthesis”Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, PergamonPress, New York, 1992.

Hydroxynitrile intermediates of Formula XV can be prepared by treatmentof ketones of Formula XVI with acetonitrile anion, formed by treatmentof acetonitrile with n-BuLi or LDA, in an inert, anhydrous solvent suchas THF at low temperature:

Amino-alcohol intermediates of Formula XII, wherein n is 0, can beprepared by treatment of sulfonate intermediates of Formula XVII,wherein R^(A) is for example methyl, trifluoromethyl or p-methylphenyl,with ammonia:

Amino-alcohol intermediates of Formula XII can be prepared by treatmentof sulfonate intermediates of Formula XVII with sodium azide to give anazide intermediate of Formula XVIII, followed by catalytic hydrogenationor by Staudinger reduction with PPh₃ in wet THF:

Sulfonate intermediates of Formula XVII can be prepared from diolintermediates of Formula XIX with a sulfonyl chloride R^(A)SO₂Cl:

Diol intermediates of Formula XIX can be prepared by hydroboration ofallyl alcohols of Formula XX:

Diol intermediates of Formula XIX can be prepared by ozonolysis andreduction of homoallyl alcohols of Formula XXI:

Aminoalcohol intermediates of Formula II, wherein A¹ is a bond, R¹ isabsent, and Cy¹ is a heteroaryl group or an aryl group bearing at leastone strongly electron withdrawing group such as CF₃, can be prepared byreaction of an aminoalcohol intermediate of Formula XII with a compoundof Formula XXII, wherein Cy¹ is a heteroaryl group or an aryl groupbearing at least one strongly electron withdrawing group such as CF₃ andR^(B) is a leaving group such a fluoro, chloro, bromo or iodo:

Aminoalcohol intermediates of Formula II, wherein A¹ is (C₁)alkylene canbe prepared by reaction of an aminoalcohol of Formula XII with analdehyde or methyl ketone of Formula XII in the presence of a reducingagent such as NaCNBH₃ or Na(OAc)₃BH:

Methods for the reductive amination of aldehydes and ketones aredescribed in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume59, Ed. Overman, L. E., Wiley Interscience, 2002.

In a second process a compound of Formula I* can be prepared by reactionof a ketocarbamate of Formula XXIV, wherein R^(D) is alkyl or arylalkylgroup such as methyl, t-butyl or benzyl, with an organometallic reagentof Formula XXV wherein M includes, but is not limited to, MgCl, MgBr,MgI or Li:

In specific examples, organometallic reagent XXV is allylmagnesiumbromide, allylzinc(II) bromide, (2-methylallyl)magnesium chloride or(2-methoxy-2-oxoethyl)zinc(II) bromide. In certain cases when M is MgCl,MgBr or MgI, it is advantageous to add CeCl₃ to the reaction mixture.

Ketocarbamates of Formula XXIV can be prepared by reaction ofaminoketones of Formula XXVI with intermediates of Formula XXVII whereinR^(E) is a leaving group such as chloride, succinyloxy, imidazolyl ort-butoxycarboxycarbonyl:

Aminoketones of Formula XXVI, wherein n=0, can be prepared by reactionof α,β-unsaturated ketones of Formula XXVIII with amines of Formula VI:

Aminoketones of Formula XXVI, wherein n=0, can be prepared by reactionof β-dialkylaminoketones of Formula XXVIII, wherein R^(F) is lower alkylespecially methyl, with amines of Formula VI:

β-Dialkylaminoketones of Formula XXVIII are in turn derived fromα,β-unsaturated ketones of Formula XXVII with dialkylamines of FormulaR^(F)NHR^(F).

In a third process a compound of Formula I* can be prepared by reactionof a compound of Formula XVII with an isocyanate of Formula XXIX in thepresence of a base:

Isocyanates of Formula XXIX can be prepared from amines of Formula VI bytreatment with phosgene, diphosgene or triphosgene. This third processis described in greater detail in U.S. Provisional Application Ser. No.61/137,013, filed Jul. 25, 2008 entitled SYNTHESIS OF INHIBITORS OF11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1, the entire teachings of whichare incorporated herein by reference.

In a fourth process a compound of Formula I* can be prepared by reactionof a halo compound of Formula, wherein Hal is chlorine or bromine, withan isocyanate of Formula XXIX in the presence of a base:

Halo compounds of Formula XXX can be prepared by reaction ofβ-haloketones of Formula XXXI with organometallic reagents of FormulaXXV wherein M is a metal containing radical including MgCl, MgBr, MgI orLi. The reaction is optionally carried out in the presence of anhydrouscerium trichloride:

In a fifth process a compound of Formula I*, wherein A¹ is CH₂ or CH₂CH₂and R¹ is absent, can be prepared by reaction of a compound of FormulaXXXII, with a compound of Formula XXXIII, wherein A¹ is CH₂ or CH₂CH₂and R^(G) is a leaving group such as Br, I, OSO₂Me, OSO₂CF₃ or OSO₂Ph,in the presence of a base such as NaH or K₂CO₃:

Compounds of Formula XXXII can be prepared by treatment of compounds ofFormula XII with various reagents of Formula III, wherein Z¹ and Z² areleaving groups such as chloride, 1-imidazolyl or aryloxide in an inertsolvent such as THF, CH₂Cl₂, toluene or MeCN, usually in the presence ofan organic or inorganic base such as triethylamine or NaHCO₃respectively, at −10° C. to 120° C.:

In a sixth process a compound of Formula I*, wherein A¹ is a bond and R1is absent, can be prepared by reaction of a compound of Formula XXXII,with a compound of Formula XXII, wherein R^(B) is a leaving group suchas chloro, bromo, iodo or OSO₂CF₃, in the presence of a base such asK₂CO₃ and a copper or palladium catalyst in an inert solvent such asdioxane, DMF or NMP at elevated temperature:

In a seventh process a compound of Formula I* can be prepared by Suzukicoupling of a compound of Formula XXXIV, wherein Cy¹ is aryl orheteroaryl and R^(X) is bromo, iodo, or trifluoromethanesulfonyloxy,with a boronic acid (R^(Y) is hydrogen) or a boronate ester of FormulaXXXV (R^(Y) is (C₁-C₆)alkyl and the two groups R^(Y) taken together forma (C₁-C₁₂)alkylene group).

In an eighth process a compound of Formula XXXIV, wherein Cy¹ is aryl orheteroaryl and R^(X) is bromo, iodo, or trifluoromethanesulfonyloxy, canbe reacted with bis(pinacolato)diboron in the presence of a palladiumcatalyst to give a boronate ester of Formula XXXVI which can be furtherreacted with a heterocyclic compound of Formula XXXVII, wherein R^(X) isbromo, iodo, or trifluoromethanesulfonyloxy, again in the presence of apalladium catalyst, to give a compound of Formula I*.

In a ninth process a compound of Formula I* can be prepared from anothercompound of Formula I*. For example:

(1) a compound of Formula I*, wherein R¹ or R³ is ω-hydroxy(C₂-C₆)alkyl,can be oxidized to a compound of Formula I*, wherein R¹ or R³ isω-carboxy(C₁-C₅)alkyl, using Jones reagent.

(2) a compound of Formula I*, wherein R¹ or R³ is ω-carboxy(C₁-C₆)alkyl,can be coupled with ammonia or a (C₁-C₆)alkylamine using a standardpeptide coupling reagent such as EDC to afford a compound of Formula I*,wherein R¹ or R³ is ω-H₂NC(═O)(C₁-C₆)alkyl orω-{(C₁-C₆)alkylNHC(═O)}(C₁-C₆)alkyl.

(3) a compound of Formula I*, wherein R¹ or R³ is ω-hydroxy(C₁-C₆)alkyl,can be converted to its methanesulfonate or trifluoromethanesulfonate,treated with sodium azide and reduced to give a compound of Formula I*,wherein R¹ or R³ is ω-amino(C₁-C₆)alkyl.

(4) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl, canbe reacted with acetic anhydride or acetyl chloride to give a compoundof Formula I*, wherein R¹ or R³ is {acetylamino}(C₁-C₆)alkyl.

(5) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl, canbe reacted with methanesulfonyl chloride to give a compound of FormulaI*, wherein R¹ or R³ is {methanesulfonylamino}(C₁-C₆)alkyl.

(6) a compound of Formula I*, wherein R¹ is (C₂-C₆)alkenyl, ishydroborated to afford a compound of Formula I*, wherein R¹ ishydroxy(C₂-C₆)alkyl.

(7) a compound of Formula I*, wherein R³ is (C₂-C₆)alkenyl, ishydroborated to afford a compound of Formula I*, wherein R³ ishydroxy(C₂-C₆)alkyl.

(8) a compound of Formula I*, wherein R¹ is (C₂-C₆)alkenyl, can bereacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford acompound of Formula I*, wherein R¹ is vicinal dihydroxy(C₂-C₆)alkyl.

(9) a compound of Formula I*, wherein R³ is (C₂-C₆)alkenyl, can bereacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford avicinal diol compound of Formula I*, wherein R³ is vicinaldihydroxy(C₂-C₆)alkyl.

(10) a compound of Formula I*, wherein R¹ is (C₂-C₆)alkenyl, can bereacted with ozone followed by NaBH₄ to give a compound of Formula I*,wherein R¹ is ω-hydroxy(C₁-C₅)alkyl.

(11) a compound of Formula I*, wherein R³ is (C₂-C₆)alkenyl, can bereacted with ozone followed by NaBH₄ to give a compound of Formula I*,wherein R³ is ω-hydroxy(C₁-C₅)alkyl.

(12) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with an (C₁-C₆)alkyl isocyanate to give a compound ofFormula I*, wherein R¹ or R³ is(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl.

(13) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with an (C₁-C₆)alkyl chloroformate to give a compound ofFormula I*, wherein R¹ or R³ is (C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl.

(14) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with chlorosulfonyl isocyanate or sulfamide to give acompound of Formula I*, wherein R¹ or R³ isaminosulfonylamino(C₁-C₆)alkyl.

(15) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with a (C₁-C₆)alkylsulfamoyl chloride to give a compoundof Formula I*, wherein R¹ or R³ is(C₁-C₆)alkylaminosulfonylamino(C₁-C₆)alkyl.

(16) a compound of Formula I*, wherein R¹ or R³ is hydroxy(C₁-C₆)alkyl,can be reacted with chlorosulfonyl isocyanate to give a compound ofFormula I*, wherein R¹ or R³ is aminosulfonyloxy(C₁-C₆)alkyl.

(17) a compound of Formula I*, wherein R¹ or R³ is hydroxy(C₁-C₆)alkyl,can be reacted with p-nitrophenyl chloroformate, pentafluorophenylchloroformate or carbonyl diimidazole, followed by ammonia, a(C₁-C₆)alkylamine or a di(C₁-C₆)alkylamine to give a compound of FormulaI*, wherein R¹ or R³ is aminocarboxy(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarboxy(C₁-C₆)alkyl or di(C₁-C₆)alkyl aminocarboxy(C₁-C₆)alkyl.

(18) a compound of Formula I*, wherein R¹ or R³ is hydroxy(C₁-C₆)alkyl,can be reacted with POCl₃ to give a compound of Formula I*, wherein R¹or R³ is (HO)₂P(═O)O(C₁-C₆)alkyl.

(19) a compound of Formula I*, wherein R³ is allyl or homoallyl, can bereacted with oxygen in the presence of PdCl₂ and CuCl to afford acompound of Formula I*, wherein R³ is 2-oxopropyl or 3-oxobutylrespectively.

(20) a compound of Formula I*, wherein R³ is 2-oxopropyl or 3-oxobutyl,can be reacted with MeMgX, wherein X is Cl, Br or I, to give a compoundof Formula I*, wherein R³ is 2-hydroxy-2-methylpropyl or3-hydroxy-3-methylpropyl respectively.

(21) a compound of Formula I*, wherein R³ is —CH₂CO₂Me can be treatedwith MeMgX, wherein X is Cl, Br or I, to give a compound of Formula I*,wherein R³ is 2-hydroxy-2-methylpropyl.

(22) a compound of Formula I*, wherein R³ is allyl or —CH₂C(Me)═CH₂, canbe hydrocyanated with TsCN in the presence of triphenylsilane andvarious cobalt catalysts to afford compounds of Formula I*, wherein R³is —CH₂CH(CN)Me or —CH₂CMe₂CN respectively.

(23) a compound of Formula I*, wherein R³ is CH₂C(Me)₂CN, can be treatedwith acetamide in the presence of PdCl₂ to give a compound of FormulaI*, wherein R³ is CH₂CMe₂CONH₂.

(24) a compound of Formula I*, wherein R³ is —CH₂C(Me)═CH₂ can betreated with m-CPBA followed by lithium triethylborohydride to afford acompound of Formula I*, wherein R³ is 2-hydroxy-2-methylpropyl.

In a tenth process, certain compounds of the invention of Formula I**are prepared as follows:

Halo compounds of Formula LIII can be formed by the treatment ofβ-haloketones of Formula XXXI with organometallic reagents of FormulaLII, wherein M denotes MgCl, MgBr, MgI, ZnBr or ZnI and the reaction isoptionally performed in the presence of anhydrous cerium trichloride inan inert anhydrous solvent, such as tetrahydrofuran, at about −25 to 0°C. for about 0.5 h.

Cyclic carbamates of Formula LIV can be prepared from the reactionbetween β-haloalcohols of Formula LIII where Hal is a chloride andisocyanates of Formula XXXIX in the presence of a base, such as but notlimited to DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in a refluxinginert solvent, such as but not limited to tetrahydrofuran.

Tertiary alcohols of Formula LVII can be derived from trisubstitutedalkenes of Formula LIV by first epoxidizing the alkene with anepoxidation reagent, such as m-CPBA (3-chloroperbenzoic acid), in aninert solvent, such as dichloromethane to produce the correspondingepoxides of Formula LV. The resulting epoxide is then reductively ringopened to provide the corresponding tertiary alcohol I* via treatmentwith a strong hydride reagent, such as lithium triethylborohydride, inan anhydrous inert solvent, such as tetrahydrofuran.

In a variation of the tenth process, a compound of the invention ofFormula I*** is prepared by using a “Suzuki” coupling reaction of aboronate ester of Formula LIX with a haloheterocycle of Formula LX.

The boronate ester of Formula LIX is prepared by reaction of a bromideof Formula LVIII with bis(pinacolato)diboron. LVIII is prepared byepoxidation of alkene LVII, followed by reductive epoxide opening asdescribed above, for 2-methyl-2-hydroxypropyl group is introduced viaepoxidation and hydride ring opening as described above for conversionof LIV to I**.

This tenth process is described in greater detail in U.S. ProvisionalApplication Ser. No. 61/137,013, filed Jul. 25, 2008 entitled SYNTHESISOF INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1, the entireteachings of which are incorporated herein by reference.

LC-MS Methods

Method 1 [LC-MS (3 min)]

Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01%TFA/water, B: 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 2.0 10 90 2.4 10 90 2.5 90 10 3.0 90 10Method 2 (10-80)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B% 0 90 10 2.2 20 80 2.5 20 80 Flow Rate 1 mL/min Wavelength UV 220 nmOven Temp 50° C. MS ESI ionizationMethod 3 (30-90)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B% 0 70 30 2.2 10 90 2.5 10 90 Flow Rate 1 mL/min Wavelength UV 220 OvenTemp 50° C. MS ESI ionizationMethod 4:

Column Waters Xbridge C18 30 × 4.6 mm 2.5 μm Mobile A: water + 0.1%F₃CCO₂H Phase B: acetonitrile TIME (min) A % B % 0 90 10 0.15 90 10 3.1510 90 4.50 10 90 4.75 20 10 5.00 20 10 Flow Rate 1.2 mL/min WavelengthUV 220, 230, or 254 nmMethod 5:

Column Merck Cromolith Speed ROD, RP18e, 50 × 4.6 mm Mobile A: water +0.1% HCO₂H Phase B: acetonitrile + 0.1% HCO₂H TIME (min) A % B % 0.00 9010 4.50 10 90 5.00 10 90 5.50 90 10 Flow Rate 1.5 mL/min Wavelength UV220, 230, or 254 nm

PREPARATION 1(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Method 1

Step 1: (S)-1-bromo-4-(1-isocyanatoethyl)benzene

To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) inmethylene chloride (3 L) and satd aq NaHCO₃ (3 L) solution was addedtriphosgene (118 g, 0.396 mol) at 0° C. The mixture was stirred for 15min. The organic phase was separated, dried over Na₂SO₄ and concentratedto give 1-bromo-4-(1-isocyanato-ethyl)-benzene (170 g, 63%).

Step 2: 1-chloro-3-phenylhex-5-en-3-ol

To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) inanhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 30min at −78° C. The reaction was quenched with aqueous NaHCO₃ solution.The organic phase was separated, dried over Na₂SO₄ and concentrated togive the crude product, which was purified by column chromatography(petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol(180 g, 86%).

¹H NMR (CDCl₃): 2.27 (m, 2H), 2.51 (m, 1H), 2.74 (m, 1H), 3.22 (m, 1H),3.58 (m, 1H), 5.16 (m, 2H), 5.53 (m, 1H), 7.23 (m, 1H), 7.39 (m, 4H).

Step 3:(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (105 g, 0.050 mmol),(S)-(−)-1-(-bromophenyl)ethyl isocyanate (170 g, 0.752 mol), and DBU(228 g, 1.5 mol) in THF (1700 mL) was heated to reflux overnight. Themixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueousphase was extracted with EtOAc (3×). The combined organic phase wasdried over Na₂SO₄. After the solvents were evaporated, the crude productwas purified by column chromatography (petroleum ether/EtOAc=20:1 to5:1) to give(R)-6-allyl-3((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(100 g, 34%). ¹H NMR (CDCl₃): 1.39 (d, 3H), 2.14 (m, 1H), 2.24 (m, 2H),2.48-2.61 (m, 3H), 2.82 (m, 2H), 5.01 (m, 2H), 5.52 (q, 1H), 5.73 (m,1H), 6.62 (d, 2H), 7.12 (m, 2H), 7.28 (m, 2H).

Step 4:(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-oneand3((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal

To a solution of(R)-6-allyl-3((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(31 g, 78 mmol) and CuCl (19.3 g, 195 mmol) in dry DMF (150 mL) wasadded H₂O (50 mL) and PdCl₂ (4.10 g, 23 mmol) at rt. After addition, themixture was stirred overnight under oxygen. After TLC showed thestarting material had disappeared, the solid was filtered off. Water(200 mL) and EtOAc (200 mL) was added, the organic layers were separatedand the aqueous layer was extracted with EtOAc (3×40 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give a residue which was purified by columnchromatography (petroleum ether/EtOAc=5:1 to 1:1) to give a mixture of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-oneand3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal,(26 g, 81%).

Step 5:(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one

To a mixture of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-oneand3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal(20 g, 48.2 mmol) in t-BuOH (250 mL) and 2-methyl-2-butene (50 mL) wasadded a solution of NaClO₂ (19.3 g, 0.213 mol) and NaH₂PO₄ (28 g, 0.179mol) in H₂O (300 mL) at 0° C. The formed mixture was stirred for 1 h at0° C. The mixture was treated with water (100 mL) and extracted withCH₂Cl₂. The combined organic layer was dried over Na₂SO₄, filtered andconcentrated to leave a residue, which was purified by columnchromatography (petroleum ether/EtOAc=5:1 to 2.5:1) to afford(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one(10.0 g, 83%). ¹H NMR (CDCl₃): 1.49 (d, 3H), 2.12 (s, 3H), 2.33 (m, 2H),2.63 (m, 1H), 2.86-3.08 (m, 3H), 5.57 (q, 1H), 6.66 (d, 2H), 7.19 (m,2H), 7.33 (m, 5H).

Step 6:(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one(20 g, 46.4 mmol) in anhydrous THF (200 mL) was added dropwisemethylmagnesium bromide (31 mL, 144 mmol) at −78° C. under nitrogen.Then the mixture was stirred at rt for 1 h. The reaction mixture wasquenched with aq NaHCO₃ (50 mL) under ice water bath. The organic layerswere separated. The aqueous layer was extracted with EtOAc (150 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purifiedcolumn chromatography (petroleum ether/EtOAc=5:1 to 2:1) to afford(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(13 g, 65%). After re-crystallization from EtOH, 4 g of the purecompound was obtained. ¹H NMR (CDCl₃): 1.06 (s, 3H), 1.12 (s, 3H), 1.44(d, 3H), 2.14 (m, 3H), 2.21 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 5.54(q, 1H), 6.74 (d, 2H), 7.16 (d, 2H), 7.28 (m, 5H).

Alternative Procedure for Method 1 Step 2

A solution of 3-chloro-1-phenylpropan-1-one (100 g, 0.595 mol) in THF(280 ml) was added dropwise to a well-stirred mixture of zinc powder(need not be activated) (40 g, 1.231 mol, satd aq NH₄Cl solution (1500ml) and THF (400 ml). Allyl bromide (143 g, 1.19 mol) was dissolved inTHF (200 ml) was slowly added to the reaction mixture. The reaction wasmildly exothermic, and the mixture began to reflux spontaneously. Afterrefluxing had ceased, the mixture was stirred for 1 h. The mixture wasextracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated togive 1-chloro-3-phenylhex-5-en-3-ol (122 g, 97%). ¹H NMR: (400 MHz,CDCl₃): δ=2.24 (s, 1H), 2.34 (m, 2H), 2.53 (m, 1H), 2.75 (m, 1H), 3.20(m, 1H), 3.58 (m, 1H), 5.18 (t, 1H), 5.51 (m, 1H), 7.26 (m, 1H),7.26-7.39 (m, 3H).

(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from (S)-1-(4-bromophenyl)propan-1-amine followingprocedures analogous to those described in Preparation 1 Method 1 Steps1 to 3 above.

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-onewas prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-onefollowing procedures analogous to those described in Preparation 1Method 1 Steps 4 and 6.

Method 2

Step 1. 1-Chloro-5-methyl-3-phenyl-hex-5-en-3-ol

To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500mL of THF (H₂O <100 ppm based on Karl Fischer titration) was charged53.0 mL of 1 M DIBAL-H in hexane under nitrogen at rt. Then3-chloro-2-methylprop-1-ene (160 g, 1.77 mol) was introduced whilemaintaining the internal temperature below 30° C. The resulting solutionwas agitated for 2 h at rt. The solution was titrated in the presence of1,1′-bipyridine to indicate 0.8 M of the corresponding Grignard reagent.To a dry flask containing 307.0 g of anhydrous CeCl₃ (1.25 mol) at rtunder nitrogen was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25mol). The resulting slurry was cooled to −10° C. and agitated for 0.5 h.To the slurry was added 200 g of 3-chloro-1-phenylpropan-1-one (1.19mol) in 200 mL of THF while maintaining the internal temperature below0° C. After the mixture was stirred for 0.5 h, 1200 mL of 1 M aq HCl wasadded to obtain a clear solution while maintaining the internaltemperature below 30° C. After the phase cut, the aqueous layer wasextracted with EtOAc (500 mL). The combined organic layers were washedwith brine and dried over sodium sulfate. Removal of the solvent undervacuum produced crude 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol, whichwas chased with THF to achieve H₂O <500 ppm based on Karl Fischertitration. The crude product (306 g, 83 wt %, 95% yield) was useddirectly in Step 3. ¹H-NMR spectroscopy (500 MHz, CDCl₃) δ 7.38-7.37 (d.J=7.8 Hz, 2H), 7.33 (t, J=7.9 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 4.91 (s,1H), 4.76 (s, 1H), 3.57 (ddd, J=5.6, 10.7, and 10.7, 1H), 3.13 (ddd,J=4.7, 10.7 and 10.7 Hz, 1H), 2.66 (d, J=13.3 Hz, 1H), 2.54 (d, J=11.3Hz, 1H), 2.53 (s, 1H), 2.36 (ddd, J=5.4, 10.6 and 13.9 Hz. 1H), 2.29(ddd, J=5.6, 11.3 and 13.3 Hz, 1H), 1.29 (s, 3H). ¹³C-NMR spectroscopy(125 MHz, CDCl₃) δ 144.3, 141.4, 128.0, 126.6, 124.8, 116.1, 74.2, 51.2,46.0, 39.9, 23.9.

Step 2. 1-Bromo-4-((S)-1-isocyanato-ethyl)-benzene

To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87mol, 2.30 equiv) and 5 L of deionized water. The resulting solution wasagitated for 10-20 min, until the solids dissolved (homogeneous). To theclear solution was charged 250 g (1.25 mol, 1.00 equiv) of(S)-(−)-1-(4-bromophenyl)ethylamine as a solution in 1.00 L ofdichloromethane. An additional 4 L of dichloromethane was charged to thereactor. The biphasic solution was agitated and cooled to T_(int)=2-3°C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactorin approximately two equal portions ˜6 min apart. It should be notedthat a slight exotherm was noted upon the addition of triphosgene. Theresulting murky solution was agitated at T_(int)=2-5° C. for 30 min, atwhich point HPLC analysis indicates >99 A % conversion (220 nm). Thedichloromethane layer was cut and dried with anhydrous sulfate. Theresulting solution was passed through a celite plug and concentrated to˜1.5 L which fine particles of a white solid developed. The solution wasfiltered and concentrated to a thick oil via reduced pressure to produce239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt %, 79.4%yield). ¹H-NMR spectroscopy (400 MHz, CD₂Cl₂) δ 7.53 (d, J=11.4 Hz, 2H),7.26 (d, J=8.2 Hz, 2H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H).The material was used in Step 3 without further purification.

Step 3.(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one

To a dried 10 L jacketed reactor under a nitrogen atmosphere was charged1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (167 g, 81.7 wt %, 610 mmol,1.00 equiv), 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (219 g, 93.7 wt%, 911 mmol, 1.50 equiv), anhydrous tetrahydrofuran (3.00 L), and then1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 mL, 2.73 mol, 4.50 equiv).The resulting solution was agitated and refluxed (T_(int)=67-69° C.,T_(ext)=75° C.) for 19 h, at which point HPLC analysis indicated ˜1A %(220 nm) of the 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol remained. Thedark solution was cooled to T_(int)=20-25° C. Two liters oftetrahydrofuran were removed by distillation under reduced pressure. Theremaining dark solution was diluted with 4.0 L of ethyl acetate and 1.0L of hexanes. The resulting solution was washed with 4.0 L of a 1.0 Maqueous solution of hydrogen chloride (note: the wash is slightlyexothermic). The aqueous solution was cut and the remaining organicsolution was dried with anhydrous sodium sulfate, filtered and thenconcentrated to an oil via reduced pressure. The resulting material wassubjected to flash silica chromatography (5-30% ethyl acetate/hexanes,1.74 kg of silica) to produce 137.8 g of material (59 wt %, 3.1:1diastereomeric ratio favoring the desired diastereomer(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one,32.3 yield). The material was used in Step 4 without furtherpurification.

Analytical data for(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one:¹H-NMR spectroscopy (500 MHz, CD₂Cl₂) δ 7.42-7.35 (m, 3H), 7.33-7.31 (m,2H), 7.25-7.23 (m, 2H), 6.80-6.74 (m, 2), 5.55 (q, J=7.1 Hz, 1H),5.37-5.36 (m, 1H), 4.89 (s, 1H), 4.69 (s, 1H), 2.96-2.93 (m, 1H), 2.61(dd, J=13.8 and 26.4 Hz, 2H), 2.37-2.25 (m, 3H), 1.68 (s, 3H), 1.50 (d,J=7.1 Hz, 3H). ¹³C-NMR spectroscopy (125 MHz, CD₂Cl₂) δ 152.5, 141.5,140.1, 138.3, 130.6, 128.1, 128.0, 126.9, 124.4, 120.2, 115.3, 82.4,52.1, 50.1, 35.6, 29.8, 23.4, 14.5.

Analytical data for(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one:¹H-NMR spectroscopy (400 MHz, CD₂Cl₂) δ 7.50-7.48 (m, 2H), 7.43-7.39 (m,2H), 7.35-7.32 (m, 3H), 7.20-7.18 (m, 2H), 5.60 (q, J=7.1 Hz, 1H), 4.85(s, 1H), 4.66 (s, 1H), 2.73-2.67 (m, 2H), 2.60 (dd, J=13.9 and 19.4 Hz,2H), 2.28 (dt, J=3.3 and 13.7 Hz, 1H), 2.14-2.05 (m, 1H), 1.66 (s, 3H),1.24 (d, J=7.2 Hz, 3H). ¹³C-NMR spectroscopy (100 MHz, CD₂Cl₂) δ 153.4,142.5, 141.0, 140.1, 131.8, 129.3, 128.9, 127.8, 125.3, 121.5, 116.3,83.9, 53.2, 51.0, 36.6, 31.3, 24.3, 15.4.

Step 4.(6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one

To a 1.0 L 2-neck RBF was charged(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol,2.0 equiv). The resulting solution was agitated at rt (T_(int)=20-25°C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion.The resulting solution was diluted with 700 mL of methyl tert-butylether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodiumthiosulfate and 1×500 mL of saturated aqueous solution of sodiumbicarbonate. The wash sequence was repeated until the peak on an HPLCtrace of the organic solution that corresponds to a HPLC sample peak ofm-CPBA is <2.5 A % (220 nm), which in this example the wash sequence wasrepeated 3 times. The resulting organic layer was dried with anhydroussodium sulfate, filtered and then concentrated to an oil via reducedpressure. The resulting material was diluted with 200 mL of anhydroustetrahydrofuran and then concentrated to a thick oil via reducedpressure to provide(6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-onewhich was used directly in Step 5.

Step 5.(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

To a 2.0 L 3-neck oven-dried RBF was charged the crude(6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-oneand 750 mL of anhydrous THF. The resulting solution was agitated andcooled to T_(int)=2-3° C. To the agitated clear solution was charged 1.0M lithium triethylborohydride in tetrahydrofuran (Super Hydride, 348 mL,348 mmol, 1.8 equiv). The addition is exothermic and addition wascontrolled to maintain T_(int)=<8° C. The resulting solution wasagitated at T_(int)=2-3° C. for 1.5 h and then allowed to warm toT_(int)=10-13° C. over a 2.5 h, which HPLC analysis indicates ˜94 A %(220 nm) conversion. To the agitated solution was charged a solution ofhydrogen peroxide (95.7 mL of a 35 wt % aqueous solution diluted with400 mL of water, 1.08 mol, 5.60 equiv). The addition is highlyexothermic and addition was controlled to maintain T_(int)=<25° C. Theresulting solution was diluted with 1.00 L of methyl tert-butyl ether(MTBE) and washed with 1.00 L of water followed by 500 mL of a ˜30 wt %solution of sodium thiosulfate. The organic solution was dried withanhydrous sodium sulfate, filtered, and then concentrated via reducedpressure. The resulting material was subjected to flash silicachromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 gof material consisting of both diastereomers (1.98:1 dr) and 41 g of thedesired diastereomer, (>99:1 dr). The material consisting of the mixedfractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g ofproduct (95.7 A % at 220 nm, 74:1 dr). The two samples were combined toproduce 72.3 g of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(83.6% yield for the two step operation). ¹H-NMR spectroscopy (400 MHz,CDCl₃) δ 7.37-7.29 (m, 5H), 7.25-7.21 (m, 2H), 6.82-6.79 (m, 2H), 5.61(q, J=6.9 Hz, 1H), 2.83 (ddd, J=2.5, 5.4 and 11.6 Hz, 1H), 2.39 (ddd,J=5.7, 12.0 and 14.1 Hz, 1H), 2.27 (ddd, J=2.6, 4.8 and 14.0 Hz, 1H),2.21-2.14 (m, 3H), 2.08 (s, 1H), 1.49 (d, J=7.0 Hz, 3H), 1.18 (s, 3H),1.13 (s, 3H). ¹³C-NMR spectroscopy (100 MHz, CDCl₃) δ 153.2, 142.6,138.5, 131.6, 129.13, 129.10, 128.0, 125.3, 121.6, 84.2, 71.4, 54.1,53.3, 36.4, 33.6, 32.1, 30.8, 15.6.

PREPARATION 2(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(6.6 g, 15.2 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.1 g, 24.3mmol) in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) andPd(dppf)cl₂ (372 mg, 0.46 mmol). After addition, the mixture was allowedto warm to 100° C. for 20 h. After TLC showed the starting material haddisappeared, the solid was filtered off. Water (60 mL) and EtOAc (20 mL)were added. The layers were separated and the aqueous layer wasextracted with EtOAc (3×15 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give aresidue, which was purified by column chromatography to give(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(4.4 g, 60%).

(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-onewas prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-onefollowing an analogous procedure.

(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-onewas prepared from(S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

(R)-6-Methoxymethyl-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-onewas prepared from3-[1-(4-bromo-phenyl)-ethyl]-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-onefollowing an analogous procedure.

PREPARATION 33-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

Preparation of Cobalt(II) Complex

A 50 mL flask was charged withN,N′-bis(3,5-di-tert-butylsalicylidene)-1,1,2,2-tetramethylethenediamine(0.430 g, 0.78 mmol, 1.0 equiv), EtOH (17 mL), and Co(OAc)₂ (0.139 g,0.78 mmol, 1.0 equiv). The mixture was degassed and then heated toreflux under nitrogen for 3 h, cooled to room temperature. Theprecipitate was filtered and the purple solid was washed with EtOH (10mL) and dried under high vacuum to give 0.353 g (75%) of the cobalt(II)complex.

A mixture of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(490 mg, 1.18 mmol), the cobalt(II) complex whose preparation isdescribed immediately above (8 mg, 0.01 equiv), TsCN (257 mg, 1.2equiv), and PhSiH₃ (137 mg, 157 μL, 1.07 equiv) in ethanol (10 mL) wasstirred 4 h at rt. After removing the solvent under reduced pressure,the residue was purified by chromatography on a 40 g silica gel column,eluted with a 25-80% EtOAc in hexanes gradient to afford3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(267 mg, 51% yield). LC-MS (3 min. method) t_(R)=1.89 min., m/z 441, 443(M+1)

PREPARATION 42,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile

3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(467 mg, 1.06 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (538 mg, 2equiv), KOAc (333 mg, 3.2 equiv), PdCl₂(dppf)CH₂Cl₂ (27 mg, 0.033 equiv)were mixed with dry DMSO (6 mL). The mixture was degassed and refilledwith N₂ gas 3 times. The mixture was then heated overnight at 90° C.under protection of N₂ gas. After being cooled to rt, the mixture wasdiluted with EtOAc (30 mL), washed with water (20 mL). The aqueous layerwas extracted with EtOAc (2×15 mL). The combined organic layers werewashed by water (15 mL), brine (2×10 mL) and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified chromatography ona 40 g silica gel column, eluted with a 20-50% EtOAc in Hexanesgradient, to afford2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile(393 mg, 76% yield).

PREPARATION 53-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrile

Method 1

Step 1. 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol

A 250-mL flask was charged with anhydrous CeCl₃ (5.58 g, 22.6 mmol) andTHF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. Thesuspension was then cooled to −78° C. and a solution of allylmagnesiumbromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one(2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reactionmixture was allowed to slowly warm to 8° C. while stirring overnight (18h). The reaction was then quenched with satd aq NaHCO₃, extracted withEtOAc, and dried over Na₂SO₄. After the solvents were evaporated, theresidue was purified by chromatography on silica gel eluted withhexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol(3.0049 g, 97%) as an oil. LC-MS Method 1 t_(R)=1.79 min, m/z 213, 211(M−OH)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H),5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H),3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃)δ −116.52 (m).

Step 2.(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-oneand(S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (0.4129 g, 1.8mmol, 1.0 equiv), (S)-(−)-1-(4-bromophenyl)ethyl isocyanate (0.5005 g,2.2 mmol, 1.2 equiv), and DBU (0.7375 g, 4.8 mmol, 2.7 equiv) in THF (10mL) was heated to reflux for 25 h. The mixture was diluted with EtOAcand washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc(2 x). The combined organic phase was dried over Na₂SO₄. After thesolvents were evaporated, the crude product was directly used in thenext step without further purification.

An analytical sample was purified by chromatography on silica gel elutedwith hexanes/EtOAc to afford the two diastereomers of6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.

Isomer 1:(S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.LC-MS Method 1 t_(R)=2.03 min, m/z 420, 418 (MH⁺); ¹H NMR (400 MHz,CDCl₃) δ 7.46 (d, J=8.2 Hz, 2H), 7.31-7.28 (m, 2H), 7.17 (d, J=8.2 Hz,2H), 7.07 (t, J=8.5 Hz, 2H), 5.76-5.66 (m, 2H), 5.10-4.99 (m, 2H),2.75-2.52 (m, 4H), 2.23-2.19 (m, 1H), 2.08-2.00 (m, 1H), 1.24 (d, J=7.0Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −115.07 (m).

Isomer 2:(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.LC-MS Method 1 t_(R)=1.98 min, m/z 420, 418 (MH⁺); ¹H NMR (400 MHz,CDCl₃) δ 7.25-7.20 (m, 4H), 7.05-7.01 (m, 2H), 6.71 (d, J=8.5 Hz, 2H),5.74-5.64 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 5.09-4.99 (m, 2H), 2.92-2.87(m, 1H), 2.63-2.50 (m, 2H), 2.33-2.16 (m, 3H), 1.47 (d, J=7.0 Hz, 3H);¹⁹F NMR (376 MHz, CDCl₃) 6-114.91 (m).

Step 3

A mixture of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(1.067 g, 2.55 mmol, 1.0 equiv), the cobalt(II) catalyst described inPreparation 3 (0.016 g, 0.0264 mmol, 0.010 equiv), TsCN (0.555 g, 3.06mmol, 1.2 equiv), and PhSiH₃ (0.294 g, 2.72 mmol, 1.07 equiv) in EtOH (5mL) was stirred at room temperature for 4 h. After the solvent wasremoved under reduced pressure, the residue was purified bychromatography on silica gel eluted with hexanes/ethyl acetate to afford1.0130 g (89%) of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrileas a solid. LC-MS t_(R)=1.83, 1.86 min in 3 min chromatography, m/z 445,447 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.22 (m, 4H), 7.13-7.05 (m,2H), 6.80-6.73 (m, 2H), 5.60-5.56 (m, 1H), 3.00-1.94 (m, 7H), 1.51-1.49(m, 3H), 1.35-1.32 (m, 1.5H), 1.27-1.24 (m, 1.5H); ¹⁹F NMR (376 MHz,CDCl₃) δ −113.08 (m), −113.69 (m).

Step 4

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrile(0.332 g, 0.746 mmol) and MeI (1.40 g, 13 equiv) in THF (12 mL) at −78°C. was added 2.4 mL (2.4 mmol, 3.2 equiv) of a 1.0 M LiHMDS solution inTHF. The resulting mixture was stirred overnight, with the temperatureslowly rising to ambient. The reaction mixture was quenched with brine(1 mL), diluted with CH₂Cl₂, and dried over Na₂SO₄. After the solventswere evaporated, the residue was purified by reversed-phase HPLC(SunFire™ Prep C₁₈ OBD™ 5 μm 19×50 mm column, 10%→90% CH₃CN/H₂O, 0.1%CF₃COOH over 8 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 2 min, flowrate 20 mL/min) to afford 0.255 g (74%) of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile.LC-MS Method 1 t_(R)=1.89 min, m/z 459, 461 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 7.31-7.27 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.83(d, J=8.2 Hz, 2H), 5.41 (q, J=7.0 Hz, 1H), 3.02-2.97 (m, 1H), 2.42-2.36(m, 1H), 2.29-2.08 (m, 4H), 1.42 (d, J=7.0 Hz, 3H), 1.30 (s, 3H), 1.22(s, 3H); ¹⁹F NMR (376 MHz, CD₃OD) δ −116.50 (m).

Method 2

Step 1

A solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (18.6 g, 0.1 mol)in THF (50 mL) was added to a well-stirred suspension of zinc power (13g, 0.2 mol) in a mixture of aqueous saturated NH₄Cl solution (260 mL)and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2mol) in THF (50 mL) was added dropwise. The reaction mixture was mildlyexothermic, and began to reflux spontaneously. After the refluxing hadceased, the mixture was stirred for 1 h. TLC showed the3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. Asolution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL)was added, and the mixture was stirred at rt overnight. The mixture wasextracted with EtOAc (2×500 mL). The combined organic layer was driedand concentrated. The residue was purified by column chromatography onsilica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) asan oil.

Step 2

A mixture of 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (3.15 g,13 mmol), (S)-(−)-1-(-bromophenyl)ethyl isocyanate (3.5 g, 16 mmol), andDBU (8 g, 33 mmol) in THF (80 mL) was heated to reflux for 25 h. Themixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueousphase was extracted with EtOAc (3×). The combined organic phase wasdried over Na₂SO₄. After the solvents were evaporated, the crude productwas purified by column to give(R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(4-fluorophenyl)-6-(2-methylallyl)-1,3-oxazinan-2-one(2.13 g, yield: 38%).

Step 3

A mixture of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-methylallyl)-1,3-oxazinan-2-one(2.13 g, 4.9 mmol), the cobalt(II) catalyst described in Preparation 3(0.032 g, 0.053 mmol), TsCN (1.11 g, 6.12 mmol), and PhSiH₃ (0.6 g, 5.54mmol) in EtOH (10 mL) was stirred at room temperature for 8 h. After thesolvent was removed under reduced pressure, the residue was purified bycolumn chromatography to give3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(1.84 g, 81.1%).

PREPARATION 63-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(730 mg, 1.59 mmol) in DMSO (8 mL) was added bis(pinacolato)diboron (480mg, 1.89 mmol), KOAc (480 mg, 4.89 mmol) and Pd(dppf)Cl₂ (45 mg, 0.042mmol) under nitrogen atmosphere. The formed mixture was stirred at 90°C. for 20 h. The reaction was quenched with water and extracted withEtOAc. The combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated to give the crude product, which was purified by columnchromatography to give3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(191 mg, 23.7%).

PREPARATION 7(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

A mixture of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(0.4910 g, 1.17 mmol, 1.0 equiv), bis(pinacolato)diboron (0.3925 g, 1.55mmol, 1.3 equiv), KOAc (0.3696 g, 3.76 mmol, 3.2 equiv), andPdCl₂(dppf).CH₂Cl₂ (0.0316 g, 0.0386 mmol, 0.033 equiv) in DMSO (6 mL)was heated at 90° C. under N₂ for 20 h. After cooling, the reactionmixture was partitioned between EtOAc and water. The organic phase waswashed with brine, and dried over Na₂SO₄. After the solvents wereevaporated, the residue was purified by chromatography on silica geleluted with hexanes/ethyl acetate to give 0.4776 g (87%) of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneas a white solid.

PREPARATION 8(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(5 g, 12.5 mmol) in tetrahydrofuran (60 mL) was added BH₃ THF (25 mL, 1mol/L, 25 mmol) at 0° C. under nitrogen atmosphere. The formed mixturewas stirred for 2 h. The reaction was quenched with water. Then NaOH (3mol/L, 10 mL) and H₂O₂ (15 mL) were added to the above mixture. When thereaction was over, the mixture was extracted with EtOAc. The combinedorganic phase was concentrated to give the crude product, which waspurified by column chromatography to give(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(2.5 g, 40%). ¹H NMR: (400 MHz, CDCl₃): δ=1.48 (t, 3H), 1.53 (m, 1H),1.73 (m, 1H), 1.93-1.98 (m, 2H), 2.17-2.28 (m, 3H), 3.57 (t, 2H), 5.59(m, 1H), 6.72 (m, 2H), 7.20 (m, 2H), 7.25-7.37 (m, 5H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-onewas prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-onefollowing an analogous procedure.

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

PREPARATION 9(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

To a solution of((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(2 g, 4.8 mmol) in DMSO (30 mL) were added bis(pinacolato)diboron (1.58g, 6.3 mmol), KOAc (1.51 g, 15.4 mmol) and PdCl₂ (130 mg, 0.16 mmol)under nitrogen atmosphere. The formed mixture was stirred at 90° C. for20 h. The reaction was quenched with water and extracted with EtOAc. Thecombined organic phase was concentrated to give the crude product, whichwas purified by column chromatography to give(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(1.7 g, 77%). ¹H NMR: (400 MHz, CDCl₃): δ=1.18 (t, 1H), 1.33 (S, 11H),1.43 (m, 2H), 1.48 (m, 3H), 1.71 (m, 1H), 1.88 (m, 2H), 2.1-2.3 (t, 3H),2.7 (m, 1H), 3.5 (m, 2H), 5.5 (m, 1H), 6.72 (m, 2H), 7.25-7.37 (m, 5H),7.48 (m, 2H).

(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-onefollowing an analogous procedure.

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

PREPARATION 10(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(methoxymethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1. 1-Methoxy-2-phenyl-pent-4-en-2-ol

2-Methoxy-1-phenyl-ethanone (5.00 g) dissolved in tetrahydrofuran (50mL) was added to 2 M allylmagnesium chloride in tetrahydrofuran (21 mL)at room temperature. The solution was stirred at room temperature for 3h and then 10% aqueous NH₄Cl solution (50 mL) was added. The resultingmixture was extracted with tert-butyl methyl ether (3×50 mL) and thecombined extracts were washed with water (50 mL) and brine (50 mL). Thesolvent was evaporated to afford the title compound as a colorless oil.Yield: 6.40 g (quantitative). Mass spectrum (ESI⁺): m/z=175 [M+H−H₂O]⁺

Step 2. 5-Methoxy-4-phenyl-pentane-1,2,4-triol

OSO₄ (4% in water, 2 mL; alternatively, K₂OsO₄ may be used) followed byN-methyl-morpholine-N-oxide (5.20 g) was added to a solution of1-methoxy-2-phenyl-pent-4-en-2-ol (1.10 g) in tetrahydrofuran (10 mL)chilled in an ice bath. The cooling bath was removed and the solutionwas stirred at room temperature overnight. Then, 10% aqueous Na₂S₂O₅solution (10 mL) was added and the resulting mixture was stirred at roomtemperature for another 1.5 h. After removal of the organic solventunder reduced pressure, the remaining mixture was extracted with ethylacetate. The combined extracts were washed with brine and dried (MgSO₄).The solvent was evaporated to afford the title compound in good purity(ca. 95%). Yield: 1.20 g (96% of theory). Mass spectrum (ESI⁻): m/z=225[M−H]⁻

Step 3. 3-Hydroxy-4-methoxy-3-phenyl-butyraldehyde

NaIO₄ (5.20 g) was added to a mixture of5-methoxy-4-phenyl-pentane-1,2,4-triol (1.10 g), dichloromethane (10mL), and water (5 mL) chilled in an ice bath. The mixture was stirredvigorously while warming to ambient temperature in the cooling bath andfurther stirred at this temperature overnight. Then, water (20 mL) anddichloromethane (50 mL) were added, the organic layer was separated, andthe aqueous layer was extracted with dichloromethane (2×25 mL). Thecombined organic phases were washed with water and dried (MgSO₄). Afterremoval of the solvent, the title compound was yielded which wasdirectly submitted to the next reaction step (glycol cleavage).

Yield: 0.94 g (quantitative)

Step 4.4-[(S)-1-(4-Bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol

(S)-1-(4-Bromo-phenyl)-ethylamine (0.93 g), NaB(OAc)₃ (0.98 g), andacetic acid (0.27 mL) were added in the given order to a solution of3-hydroxy-4-methoxy-3-phenyl-butyraldehyde (0.90 g) in tetrahydrofuran(20 mL) at ca. 10-15° C. The cooling bath was removed and the mixturewas stirred at room temperature for 2 h. Then, water (50 mL) and 1 Maqueous NaOH solution (20 mL) were added and the resulting mixture wasstirred for another 30 min. The mixture was extracted with ethyl acetateand the combined extracts were washed with water and brine. After drying(MgSO₄), the solvent was removed to give the title compound which wassubmitted to the subsequent reaction step without further purification.Yield: 1.80 g (quantitative). Mass spectrum (ESI⁺): m/z=378/380 (Br)[M+H]⁺

Step 5.3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-oneand3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-one

Triphosgene (157 mg) was added to an ice-cold solution of4-[(S)-1-(4-bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol (1:1diastereomeric mixture, 200 mg) and EtNiPr₂ (91 μL) in dichloromethane(5 mL). The resulting solution was stirred with cooling for 2 h and atroom temperature overnight. Then, the solution was concentrated underreduced pressure and the residue was purified by HPLC on reversed phase(MeCN/H₂O/NH₃) to afford the title compounds in separate fractions.

Isomer 1:3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-one.Yield: 45 mg (21% of theory). Mass spectrum (ESI⁺): m/z=404 [M+H]⁺¹H NMR(400 MHz, DMSO-d₆) δ 1.41 (d, J=7.1 Hz, 3H), 2.19 (td, J=11.2, 5.2 Hz,1H), 2.24-2.34 (m, 1H), 2.34-2.41 (m, 1H), 3.02-3.09 (m, 1H), 3.27 (s,3H), 3.49 (d, B part of an AB signal, J=10.6 Hz, 1H), 3.53 (d, A part ofan AB signal, J=10.6 Hz, 1H), 5.34 (q, J=7.0 Hz, 1H), 6.80 (dm, J=8.4Hz, 2H), 7.27 (dm, J=8.4 Hz, 2H), 7.32-7.42 (m, 5H).

Isomer 2:3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-one.Yield: 45 mg (21% of theory). Mass spectrum (ESI⁺): m/z=404 [M+H]⁺¹H NMR(400 MHz, DMSO-d₆) δ 1.20 (d, J=7.2 Hz, 3H), 2.13-2.23 (m, 1H),2.32-2.40 (m, 1H), 2.63-2.72 (m, 1H), 2.73-2.81 (m, 1H), 3.26 (s, 3H),3.48 (d, B part of an AB signal, J=10.6 Hz, 1H), 3.55 (d, A part of anAB signal, J=10.6 Hz, 1H), 5.35 (q, J=7.2 Hz, 1H), 7.19 (dm, J=8.4 Hz,2H), 7.32-7.45 (m, 5H), 7.53 (dm, J=8.4 Hz, 2H).

PREPARATION 11N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide

Step 1

To a solution of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(200 mg, 0.48 mmol) in CH₂Cl₂ (5 mL) was added Et₃N (240 mg, 2.4 mmol)and methanesulfonyl chloride (164 mg, 1.4 mmol) at 0° C. The reactionsolution was stirred at rt for 1 h. The reaction was quenched with H₂Oand the mixture was extracted with CH₂Cl₂. The organic phase wasconcentrated to give3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propylmethanesulfonate (234 mg, 98%), which was used for the next step withoutfurther purification.

Step 2

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propylmethanesulfonate (234 mg, 0.24 mmol) in CH₂Cl₂ (3 mL) was added NaH (82mg, 3.4 mmol) at 0° C. The mixture was stirred at rt for 30 min. ThenN-methylacetamide (204 mg, 2.8 mmol) was added the above mixture. Theformed mixture was stirred at 80° C. for 5 h. After the reaction wasover, the reaction was quenched with water and the mixture was extractedwith EtOAc. The combined organic phase was concentrated to give thecrude product, which was purified by preparative TLC to giveN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide(150 mg, 68%). LC-MS Method 2 t_(R)=1.50 min, m/z=497, 495, 475, 473. ¹HNMR (400 MHz, CDCl₃): δ=1.41 (m, 1H), 1.48 (t, 3H), 1.73 (m, 1H),1.83-1.95 (m, 2H), 2.01 (m, 3H), 2.1-2.3 (m, 3H), 2.71 (m, 1H), 2.81 (s,3H), 3.1 (m, 1H), 3.2 (m, 1H), 5.5 (m, 1H), 6.72 (m, 2H), 7.10 (m, 2H),7.20 (m, 2H), 7.37 (m, 3H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure using pyrrolidin-2-one in Step 2.

PREPARATION 12(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(3 g, 7.5 mmol) in CH₂Cl₂ (50 mL) was treated with O₃ at −78° C. tillthe mixture turned blue. Then NaBH₄ (285 mg, 75 mmol) was added to thesolution at 0° C., and the reaction solution was stirred at roomtemperature for 3 hours. The reaction was quenched by H₂O, and themixture was extracted with EtOAc. The combined organic phase wasconcentrated to give the crude product, which was purified bypreparative TLC to give(S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one(2.5 g, 84%). ¹H NMR (CDCl₃): 1.48 (t, 3H), 2.05-2.41 (m, 4H), 2.71-2.92(m, 2H), 3.51 (m, 1H), 3.71 (m, 1H), 5.58 (m, 1H), 6.73 (d, 2H), 7.12(m, 2H), 7.23-7.45 (m, 6H).

(S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-onefollowing a procedure analogous to that described immediately above.

PREPARATION 13(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one(300 mg, 0.75 mmol) in dichloromethane (20 mL) were added Et₃N (390 mg,3.75 mmol) and methanesulfonyl chloride (256 mg, 2.25 mmol) at 0° C. Thereaction solution was stirred at rt for 1 h. The reaction was quenchedwith H₂O and the mixture was extracted with dichloromethane. The organicphase was concentrated to give2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl-methanesulfonate (352.8 mg, 98%), which was used for the next step withoutfurther purification.

Step 2

To a solution of2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl-methanesulfonate(360 mg, 0.75 mmol) and K₂CO₃ (207 mg, 1.5 mmol) in acetonitrile (10 mL)was added isothiazolidine 1,1-dioxide (121 mg, 4.6 mmol), and themixture was refluxed overnight. The mixture was filtered and thefiltrate was concentrated to give the crude product, which was purifiedby preparative HPLC to afford compound(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one(2.43 mg, 1%). LC-MS Method 2 t_(R)=1.37 min, m/z=509, 507. ¹H NMR(CDCl₃): 1.48 (t, 3H), 2.05-2.41 (m, 7H), 2.71-2.92 (m, 2H), 3.11 (m,3H), 3.21 (m, 2H), 5.58 (m, 1H), 6.73 (d, 2H), 7.18 (m, 1H), 7.23 (m,3H); 7.35 (m, 3H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(1,1-dioxo-isothiazolidin-2-yl)propyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

PREPARATION 14(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one

Step 1

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(450 mg, 1.01 mmol) in acetone (10 mL) was added a solution of KMnO₄(190 mg, 1.2 mmol) and NaIO₄ (1.5 g, 7.2 mmol) in water (10 mL). Themixture was stirred for 2 h at 0° C. The mixture was filtered and thefiltrate was adjusted to pH 5-6 with aqueous 1 N aq HCl solution. Themixture was extracted with EtOAc. The organic phase washed with brine,dried over anhydrous Na₂SO₄ and concentrated to give2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)aceticacid (540 mg, crude), which was used for the next step withoutpurification.

Step 2

To a solution of2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)aceticacid (540 mg, 1.24 mol) in MeOH (20 mL) was added SOCl₂ (5 mL) at 0° C.,and the reaction mixture was stirred at rt for 2 h. The reaction mixturewas concentrated and the residue was purified by preparative TLC to givemethyl2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate(150 mg, 27%). ¹H NMR (CDCl₃): δ=1.49 (d, 3H), 2.19 (m, 1H), 2.44 (m,1H), 2.60 (m, 1H), 2.77-3.08 (m, 3H), 3.51 (s, 3H), 5.52 (m, 2H), 6.62(d, 2H), 6.98 (t, 2H), 7.23 (t, 2H), 7.28 (m, 2H).

Step 3

To a solution of methyl2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate(150 mg, 0.33 mmol), and tetraisopropoxytitanium (189 mg, 0.66 mmol) inTHF (20 mL) was added 3.0 Methylmagnesium bromide (4 mL, 12 mmol) at rtunder nitrogen. Then the mixture was stirred for 2 h. The reaction wasquenched with aqueous NH₄Cl solution, and the mixture was filtered. Thefiltrate was extracted with EtOAc. The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated to give thecrude product, which was purified by preparative HPLC to give(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one(2.51 mg, 2%). ¹H NMR (CDCl₃): 0.03 (m, 1H), 0.18 (m, 1H), 0.49 (m, 1H),0.60 (m, 1H), 1.43 (m, 3H), 2.08 (s, 2H), 2.26 (m, 1H), 2.37 (m, 2H),2.88 (m, 1H), 5.53 (m, 1H), 6.66 (d, 2H), 6.97 (t, 2H), 7.16 (m, 2H),7.26 (m, 2H).

PREPARATION 15N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylmethanesulfonamide

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl methanesulfonate (180 mg, 0.36 mmol) in DMF (5 mL) was added NaH(14.6 mg, 0.36 mmol) at 0° C. The mixture was stirred at rt for 30 min.Then iodomethane (153 mg, 1.1 mmol) was added to the above mixture. Theformed mixture was stirred at 40° C. for 3 h. After the reaction wasover, the reaction was quenched with NH₄Cl solution and the mixture wasextracted with EtOAc. The combined organic phase was concentrated togive the crude product, which was purified by preparative TLC to giveN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylmethanesulfonamide(100 mg, 55%). LC-MS Method 2 t_(R)=1.41 min, m/z=511, 509. ¹H NMR (400MHz, CDCl₃): δ=1.45 (m, 1H), 1.48 (t, 3H), 1.83-1.97 (m, 3H), 2.1-2.2(m, 3H), 2.61 (s, 3H), 2.71 (s, 3H), 2.91 (m, 1H), 3.0 (m, 2H), 5.5 (m,1H), 6.72 (m, 2H), 7.10 (m, 2H), 7.20 (m, 2H), 7.37 (m, 3H).

EXAMPLE 1(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(112 mg, 0.259 mmol) in 1,4-dioxane (3 mL) was added6-oxo-1,6-dihydropyridin-3-ylboronic acid (55 mg, 0.40 mmol), followedby Pd(dppf)Cl₂ (11 mg, 0.015 mmol), and an aq solution of Cs₂CO₃ (0.48mL, 2M in H₂O). A reflux condenser was attached and the apparatus wasdegassed and flushed with N₂ three times. The reaction was heated to 90°C. for 24 h. After cooling to rt the mixture was diluted with water andextracted three times with EtOAc. The organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by prep HPLC to afford the title compounds (21.6 mg) as an oil.LC-MS Method 1 t_(R)=1.25 min, m/z=447, 389; ¹H NMR (CD₃OD) 0.96 (s,3H), 1.28 (s, 3H), 1.57 (d, 3H), 2.16 (s, 2H), 2.21 (m, 1H), 2.46 (m,2H), 3.03 (m, 1H), 5.57 (q, 1H), 6.66 (d, 1H), 7.02 (d, 2H), 7.25-7.40(7H), 7.66 (s, 1H), 7.90 (d, 1H).

EXAMPLE 2(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-iodopyridin-2(1H)-one following a procedure analogous to thatdescribed in Example 1. LC-MS Method 1 t_(R)=1.23 min, m/z=389, 447(M+1); ¹H NMR (CD₃OD) 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H),7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q,J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H),2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).

EXAMPLE 3(S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Step 1. 5-bromo-1-cyclopropylpyridin-2(1H)-one

A mixture of 5-bromo-2-hydroxypyridine (0.8300 g, 4.77 mmol, 1.0 equiv),Cu(OAc)₂ (0.902 g, 4.96 mmol, 1.04 equiv), bipyridine (0.785 g, 5.03mmol, 1.05 equiv), cyclopropylboronic acid (0.846 g, 9.85 mmol, 2.06equiv) and Na₂CO₃ (1.110 g, 10.47 mmol, 2.20 equiv) in dichloroethane(30 mL) was stirred at 70° C. for 22 h under air. The reaction mixturewas quenched with satd aq NH₄Cl, diluted with CH₂Cl₂, dried over Na₂SO₄.After the solvent was removed under reduced pressure, the residue waspurified by chromatography on silica gel eluted with hexanes/EtOAc toafford 0.585 g (58%) of 5-bromo-1-cyclopropylpyridin-2(1H)-one. LC-MSMethod 1 t_(R)=1.05 min, m/z 214, 216 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ7.41 (d, J=2.7 Hz, 1H), 7.31 (dd, J=9.7, 2.9 Hz, 1H), 6.47 (d, J=9.9 Hz,1H), 3.33-3.27 (m, 1H), 1.17-1.12 (m, 2H), 0.89-0.84 (m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 162.58, 142.29, 137.00, 121.77, 97.92, 32.83, 6.93.

Step 2.(S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(0.729 g, 1.52 mmol) in 1,4-dioxane (16 mL) were added5-bromo-1-cyclopropylpyridin-2(1H)-one (0.323 g, 1.51 mmol), 2 M aqCs₂CO₃ (4 mL), and PdCl₂(dppf).CH₂Cl₂ (0.079 g, 0.0964 mmol). Themixture was degassed and heated, under a nitrogen atmosphere, at 120° C.for 16 h. The mixture was diluted with CH₂Cl₂, dried over Na₂SO₄. Afterthe solvents were evaporated, the residue was purified by chromatographyon silica gel eluted with MeOH/CH₂Cl₂ to afford 0.543 g (74%) of(S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one.LC-MS Method 1 t_(R)=1.41 min, m/z 487 (MH⁺);

¹H NMR (400 MHz, CD₃OD) δ 7.66-7.64 (m, 2H), 7.30-7.19 (m, 7H), 6.94 (d,J=8.2 Hz, 2H), 6.52 (d, J=10 Hz, 1H), 5.48 (q, J=7.0 Hz, 1H), 3.32-3.26(m, 1H), 2.97-2.92 (m, 1H), 2.46-2.32 (m, 2H), 2.16-2.09 (m, 1H), 2.08(s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 1.10-1.05 (m, 2H),0.90-0.86 (m, 5H); ¹³C NMR (100 MHz, CD₃OD) δ 165.59, 155.82, 144.08,141.05, 139.60, 136.60, 136.30, 129.77, 128.86, 128.64, 126.83, 126.15,121.93, 120.53, 85.33, 71.67, 55.18, 54.78, 37.46, 34.10, 33.04, 31.79,30.00, 15.60, 7.49, 7.47.

EXAMPLE 4(S)-3-((S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

A microwave vial equipped with a flea stirbar was charged with(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(20 mg, 0.047 mmol), 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one (25 mg,0.113 mmol), Cs₂CO₃ (27 mg, 0.083 mmol), H₂O (0.1 mL) and dry dioxane (1mL). The mixture was sparged with N₂ for 10 min and heated at 110° C. inthe microwave for 0.5 h. The mixture was diluted with glacial HOAc (0.1mL) and MeOH (0.5 mL) and filtered. The filtrate was directly purifiedby prep HPLC to afford(S)-3-((S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(11.8 mg, 57%) as an oil. LC-MS Method 1 t_(R)=1.55 min, m/z=497, 248;¹H NMR (CDCl₃) 1.13 (s, 3H), 1.19 (s, 3H), 1.56 (d, 3H), 2.15-2.35 (s,4H), 2.42 (m, 2H), 2.88 (m, 1H), 5.71 (q, 1H), 6.64 (d, 1H), 7.04 (d,2H), 7.18 (d, 2H), 7.30-7.40 (5H), 7.52 (1H), 7.60 (m, 1H), 7.75 (t,1H).

5-bromo-1-(difluoromethyl)pyridin-2(1H)-one was prepared as described inAndo, M.; Wada, T.; Sato, N. Org. Lett. 2006, 8, 3805-3808.

EXAMPLE 5(S)-3-((S)-1-(4-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

A stirred mixture of 2-chloro-4-iodopyridine (1.33 g, 5.6 mmol) andpowdered NaHCO₃ (935 mg, 11.2 mmol) in MeCN (2 mL) was warmed to 40° C.in an oil bath and a solution of 2,2-difluoro-2-(fluorosulfonyl)aceticacid (0.57 mL, 5.6 mmol) in MeCN (10 mL) was added dropwise over 10 min.The mixture was stirred at 40° C. for 2 h. LC-MS showed partialconversion to desired product. Powdered NaHCO₃ (935 mg, 11.2 mmol) wasadded followed by a solution of 2,2-difluoro-2-(fluorosulfonyl)aceticacid (0.57 mL, 5.6 mmol) in MeCN (10 mL) dropwise over 10 min. Themixture was stirred at 40° C. for 2 h. The mixture was diluted with satdaq NaHCO₃ (25 mL) and concentrated under reduced pressure. The aqueousresidue was extracted with EtOAc (90 mL). The organic extract was washedwith brine (20 mL), dried over Na₂SO₄ and concentrated to afforded anamber oil (1.14 g). Chromatography on a 40-g silica gel cartridge,eluted with a 0-40% EtOAc in hexanes gradient, afforded1-(difluoromethyl)-4-iodopyridin-2(1H)-one (255 mg, yield 16%, estimatedpurity 45%) as yellow oil. LC-MS Method 1 t_(R)=1.23 min, m/z=272. Thematerial was used without further purification.

Step 2

A microwave vial equipped with a flea stir bar was charged with(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(52 mg, 0.11 mmol), 1-(difluoromethyl)-4-iodopyridin-2(1H)-one (29 mg,0.11 mmol), Cs₂CO₃ (71 mg, 0.22 mmol), H₂O (0.1 mL) and dry dioxane (1mL). The mixture was sparged with N₂ for 5 min and PdCl₂(dppf) (5 mg,0.007 mmol) was added. The mixture was sparged with N₂ for 5 min andheated at 110° C. in the microwave for 1 h. The mixture was diluted with5% aq HCl (0.2 mL) and MeOH (2 mL) and filtered. The filtrate wasdirectly purified by prep HPLC to afford a brown oil (16.2 mg) which wasapplied to a 2-g silica SPE cartridge which was eluted sequentially with25 and 50% EtOAc in hexanes (15 mL of each) and EtOAc (3×15 mL) toafford five fractions. Fractions 3 and 4 were pooled and concentrated toafford(S)-3-((S)-1-(4-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(13.4 mg, 25%) as a colorless oil. LC-MS Method 1 t_(R)=1.57 min,m/z=497, 439; ¹H NMR (CD₃OD) 0.96 (s, 3H), 1.27 (s, 3H), 1.56 (d, 3H),2.15 (s, 2H), 2.21 (m, 1H), 2.40-2.60 (2H), 3.08 (m, 1H), 5.59 (q, 1H),6.66 (s, 1H), 6.74 (d, 1H), 7.07 (d, 2H), 7.30-7.40 (5H), 7.45 (d, 2H),7.77 (1H), 7.79 (t, 1H).

EXAMPLE 62,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

Step 1

A mixture of2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile(392 mg, 0.775 mmol), 5-bromo-1-methylpyridin-2(1H)-one (220 mg, 1.5equiv), 2M aq Cs₂CO₃ solution (900 μL), Pd(PPh₃)₂Cl₂ (40 mg, 7 mol %)and anhydrous 1,4-dioxane (8.5 mL) was degassed and refilled with N₂ gas3 times. The mixture was then heated overnight at 85° C. underprotection of N₂ gas. After being cooled to rt, the mixture was dilutedwith EtOAc (20 mL), washed by water (20 mL). The aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were washedby water (10 mL), brine (2×10 mL) and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by Gilson toafford 34 mg product (9% yield). LC-MS (3 min. method) t_(R)=1.44 min.,m/z 470 (M+1). ¹H NMR (CDCl₃) δ 7.68 (dd, 1H), 7.52 (d, 1H), 7.31 (q,2H), 7.16 (d, 2H), 7.07 (t, 2H), 6.97 (d, 2H), 6.91 (d, 1H), 5.66 (q,1H), 3.71 (s, 3H), 2.99 (dt, 1H), 2.47 (dd, 2H), 2.27 (m, 1H), 2.13 (s,2H), 1.55 (d, 3H), 1.44 (s, 3H), 1.24 (s, 3H).

Step 2

A THF:H₂O (2 mL, 3:1) solution of2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile(55 mg, 0.12 mmol), acetamide (177 mg, 3 mmol) and PdCl₂ (21 mg, 0.12mmol) was stirred overnight. The solvent was removed and the crudematerial redissolved in CH₃CN. The crude product was purified via prepHPLC to afford2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide(28 mg). LC-MS Method 1 t_(R)=1.25 min, m/z=488 (M+1); ¹H NMR (CDCl₃)7.55 (dd, 1H, J=9 Hz, 3 Hz), 7.42 (d, 1H, J=3 Hz), 7.32 (d, 1H, J=4 Hz),7.29 (m, 4H), 7.14 (d, 2H, 8 Hz), 7.00 (d, 2H, J=8 Hz), 6.79 (d, 1H, J=9Hz), 5.66 (q, 1H, J=8 Hz), 3.62 (s, 3H), 2.95-2.89 (m, 1H), 2.5 (d, 1H,J=15 Hz), 2.26-2.1 (m, 3H), 2.2 (d, 1H, J=15 Hz), 2.5 (d, 1H, J=15 Hz),2.26-2.10 (m, 3H), 2.2 (d, 1H, J=15 Hz), 1.53 (d, 3H, J=7 Hz), 1.22 (s,3H), 1.20 (s, 3H)

EXAMPLE 7(S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

A foil covered flask charged with2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide(20 mg, 0.04 mmol) in 1:1 CH₃CN/H₂O (1 mL) was treated with PhI(O₂CCF₃)₂(31 mg, 0.07 mmol). The reaction was complete after 24 h. The solventwas removed and the crude material purified by prep HPLC to afford(S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(16 mg). LC/MS ES+=460 (M+1). LC-MS Method 1 t_(R)=1.06 min, m/z=460(M+1); ¹H NMR (CDCl₃) 7.60 (dd, 1H, J=9 Hz, 2 Hz), 7.46 (d, 1H, J=3 Hz),7.39-7.27 (m, 5H), 7.20 (d, 2H, J=7 Hz), 7.1 (d, 2H, J=8 Hz), 6.78 (d,1H, J=9 Hz, 5.61 (q, 1H, J=7 Hz), 3.65 (s, 3H), 2.87 (m, 1H), 2.80 (d,1H, J=16 Hz), 2.23 (d, 1H, J=16 Hz), 2.19-2.08 (m, 3H), 1.54 (d, 3H, J=7Hz), 1.41 (s, 3H), 0.96 (s, 3H).

EXAMPLE 8N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)acetamide

A CH₂Cl₂ (1 mL) solution of(S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(5 mg, 0.009 mmol) was treated with DMAP (5 mg, 0.04 mmol), i-Pr₂NEt (10drops), and acetic anhydride (20 drops). The reaction was stirredovernight. The reaction solution was washed with water. The organiclayer was evaporated and the crude material purified by prep HPLCaffordingN-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)acetamide(0.88 mg). LC-MS Method 1 t_(R)=1.3 min, m/z=502 (M+1).

EXAMPLE 9 Methyl2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-ylcarbamate

A CH₂Cl₂ (1 mL) solution of(S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(5 mg, 0.009 mmol) was treated with DMAP (5 mg, 0.04 mmol), i-Pr₂NEt (10drops), and methyl chloroformate (20 drops). The reaction was stirredovernight. The reaction solution was by prep HPLC affording methyl2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-ylcarbamate(2.58 mg). LC-MS Method 1 t_(R)=1.45 min, m/z=518 (M+1); ¹H NMR (CDCl₃)7.66 (dd, 1H, J=9 Hz, 2 Hz), 7.48 (d, 1H, J=3 Hz), 7.35-7.27 (m, 5H),7.15 (d, 2H, J=8 Hz), 7.01 (d, 2H, J=8 Hz), 6.87 (d, 1H, J=9 Hz), 5.67(q, 1H, J=7 Hz), 3.69 (s, 3H), 2.2 (s, 3H), 1.54 (d, 3H, J=7 Hz),1.46-1.36 (m, 2H), 1.30 (s, 3H), 1.20 (s, 3H).

EXAMPLE 10N-(2-methyl-1-((S)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide

The title compound was prepared fromN-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)methanesulfonamideand 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedureanalogous to that described in Example 4. LC-MS Method 1 t_(R)=1.3 min,m/z=524 (M+1); ¹H NMR (CDCl₃) 7.81 (d, 1H, J=9 Hz), 7.63 (br s, 1H),7.39-7.31 (m, 5H), 7.18 (d, 2H, J=8 Hz), 7.03 (d, 2H, J=7 Hz), 6.79 (d,1H, J=9 Hz), 5.67 (q, 1H, J=6 Hz), 2.93 (s, 3H), 2.90 (m, 1H), 2.49 (d,1H, J=15 Hz), 2.32 (d, 1H, J=15 Hz), 2.28-2.18 (m, 3H), 1.54 (d, 3H, J=7Hz), 1.36 (s, 3H), 1.25 (s, 3H).

N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)methanesulfonamidewas prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrileby sequential application of procedures analogous to those described inExamples 6 Step 2, Example 7 and Example 11.

EXAMPLE 11N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide

A CH₂Cl₂ (1 mL) solution of(S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(5 mg, 0.009 mmol) was treated with DMAP (5 mg, 0.04 mmol), i-Pr₂NEt (10drops), and MsCl (20 drops). The reaction was stirred overnight. Thereaction solution was washed with water. The organic layer wasevaporated and the crude material purified by prep HPLC affordingN-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide(3.30 mg). LC-MS Method 1 t_(R)=1.39 min, m/z=538 (M+1); ¹H NMR (CDCl₃)7.61 (dd, 1H, J=9 Hz, 3 Hz), 7.46 (d, 1H, J=2 Hz), 7.40-7.27 (m, 5H),7.17 (d, 2H, J=8 Hz), 7.04 (d, 2H, J=8 Hz), 6.79 (d, 1H, J=9 Hz), 5.67(q, 1H, J=7 Hz), 3.66 (s, 3H), 2.93 (s, 3H), 2.31-2.22 (m, 2H), 1.55 (d,3H, J=7 Hz), 1.48-1.36 (m, 2H), 1.33 (s, 3H), 1.24 (s, 3H).

EXAMPLE 12N-methyl-N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide

To a rt solution ofN-(2-methyl-1-((S)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide(7 mg, 0.013 mmol) in THF, NaH (10 mg, 0.20 mmol) was added followed bymethyl iodide (30 uL, 0.080 mmol). The reaction was heated to 60° C. for5 h. The flask was cooled to rt then to 0° C. before quenching with satdaq NH₄Cl. The mixture was extracted with EtOAc (3×) and the combinedorganic layers were dried over Na₂SO₄, filtered, evaporated and purifiedby prep HPLC to affordN-methyl-N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide(4.63 mg). LC-MS Method 1 t_(R)=1.45 min, m/z=552 (M+1); ¹H NMR (CDCl₃)7.55 (dd, 1H, J=9 Hz, 3 Hz), 7.41 (d, 1H, J=3 Hz), 7.35-7.27 (m, 5H),7.13 (d, 2H, J=8 Hz), 6.98 (d, 2H, J=8 Hz), 6.79 (d, 1H, J=9 Hz), 6.55(q, 1H, J=7 Hz), 3.62 (s, 3H), 2.91-2.86 (m, 1H), 2.86 (s, 3H), 2.73 (d,1H, J=15 Hz), 2.74 (s, 3H), 2.46 (d, 1H, J=15 Hz), 2.39-2.36 (m, 2H),2.25-21.6 (m, 1H), 1.53 (d, 3H, J=7 Hz), 1.53 (s, 3H), 1.22 (s, 3H).

EXAMPLE 13N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide

Step 1

To a solution of3-(R-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(1 g, 2.27 mmol) in a mixture of THF/H₂O (3:1, 10 mL) was addedacetamide (3.35 g, 56.75 mmol) and PdCl₂ (0.402 g, 2.27 mmol). Thereaction was stirred overnight. The solvent was removed, and the residuewas purified by TLC to afford3-(R-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanamide(0.745 g, 71.6%).

Step 2

To a solution of3-(R-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanamide(0.74 g, 1.612 mmol) in a mixture of CH₃CN/H₂O (20 mL, 1:1) was addedPhI(OC₂CCF₃)₂ (1.178 g, 2.74 mmol). The mixture reaction was stirredovernight. The mixture was extracted with EtOAc (30 mL). The organiclayer was washed with brine, and concentrated to affordS-6-(2-amino-2-methylpropyl)-3-S-1-(4-bromophenyl)-ethyl)-6-phenyl-1,3-oxazinan-2-one(0.6 g, 87%).

Step 3

To a solution ofS-6-(2-amino-2-methylpropyl)-3-S-1-(4-bromophenyl)-ethyl)-6-phenyl-1,3-oxazinan-2-one(0.6 g, 1.39 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.84 g, 8.34 mmol).The mixture was cooled at 0° C., MsCl (0.48 g, 4.17 mmol) was added. Thereaction was stirred at rt for 1 h. The mixture was evaporated to affordthe crude product. The residue was purified by column to affordN-1-S-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)-methyl-sulfonamide(0.5 g, 70.4%).

Step 4

To a solution ofN-1-S-3-S-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)-methyl-sulfonamide(0.5 g, 0.98 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-(1,3,2-dioxaborolane) (0.399 g,1.57 mmol) in dry DMSO (15 mL) was added KOAc (0.31 g, 3.14 mmol) andPd(dppf)Cl₂ (0.025 g, 0.03 mmol) under N₂ atmosphere. After addition,the mixture was stirred at 90° C. overnight. After TLC showed thestarting material had disappeared, the solid was filtered off. Water (30mL) and EtOAc (50 mL) was added, the mixture was extracted with EtOAc(3×30 mL). The combined organic layer was washed with brine (50 mL),dried over Na₂SO₄, filtered, and concentrated to dryness. The residuewas purified by column chromatography to affordN-(2-methyl-1-S-2-oxo-6-phenyl-3-S-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propan-2-yl)-methyl-sulfonamide(0.2 g, yield: 37%).

Step 5

To a solution ofN-(2-methyl-1-S-2-oxo-6-phenyl-3-S-1-4-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propan-2-yl)-methylsulfonamide (150 mg, 0.27 mmol) and 4-iodo-1-methylpyridin-2(1H)-one indry 1,4-dioxane (5 mL) was added Cs₂CO₃ (0.3 mL, 6 mmol) and Pd(PPh₃)Cl₂(20 mg). After addition, the mixture was warmed at 110° C. for 2 min.After TLC showed the starting material had disappeared, the solid wasfiltered off. Water (20 mL) and EtOAc (30 mL) were added. The organiclayer was separated, and the aqueous layer was extracted with EtOAc(3×30 mL). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated to give the crude product, which waspurified by preparative HPLC to provideN-2-methyl-1-S-3-S-1-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-phenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)methyl sulfonamide (20 mg, 14%). LC-MS Method 2 t_(R)=1.154min, m/z=538.1; ¹H NMR (CDCl₃): δ1.25 (s, 3H), 1.32 (s, 3H), 1.55 (d,3H), 2.50 (d, 2H), 2.91 (s, 3H), 3.63 (s, 3H), 4.54 (b, 1H), 5.67 (m,1H), 6.53 (d, 1H), 6.92 (s, 1H), 7.06 (d, 2H), 7.30-7.50 (m, 8H).

EXAMPLE 142,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 4-iodopyridin-2(1H)-one following a procedure analogous to thatdescribed in Example 4. LC-MS Method 1 t_(R)=1.36 min, m/z=456(M+1); ¹HNMR (CDCl₃) 7.77 (d, 1H), 7.43-7.32 (m, 7H), 7.01 (t, 4H), 5.67 (q, 1H),2.99 (dd, 1H), 2.57-2.43 (m, 2H), 2.32 (m, 1H), 2.17 (s, 2H), 1.57 (d,3H), 1.40 (s, 3H), 1.33 (s, 3H).

EXAMPLE 153-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrileand 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedureanalogous to that described in Example 4. LC-MS Method 1 t_(R)=1.37 min,m/z=474(M+1); ¹H NMR (CDCl₃) 7.97, (dd, 1H), 7.73 (s, 1H), 7.33 (m, 2H),7.20 (d, 2H), 7.17 (t, 2H), 6.98 (m, 3H), 5.67 (q, 1H), 3.00 (dt, 1H),2.49 (m, 2H), 2.30 (m, 1H), 2.13 (s, 2H), 1.55 (d, 3H), 1.45 (s, 3H),1.34 (s, 3H).

EXAMPLE 163-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

A mixture of3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(100 mg, 0.21 mmol) and 4-iodo-1-methyl-1H-pyridin-2-one (40 mg, 0.17mmol), Pd(PPh₃)₂Cl₂ (20 mg), and aq. Cs₂CO₃ solution (2.0 mL, 2M) in1,4-dioxane (5 mL) was stirred at reflux for 2 h. The organic phase wasseparated and concentrated to give the crude product, which was purifiedby preparative TLC to give3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(55 mg, 66%). LC-MS Method 2 t_(R)=1.096 min, m/z=488.3; ¹H NMR (CDCl₃):δ 1.27 (s, 3H), 1.40 (s, 3H), 1.48 (d, 3H), 2.06 (s, 2H), 2.23 (m, 1H),2.41 (m, 2H), 2.90 (m, 1H), 3.51 (s, 3H), 5.60 (m, 1H), 6.27 (m, 1H),6.65 (d, 1H), 6.89 (d, 2H), 6.99 (t, 2H), 7.26 (m, 5H).

EXAMPLE 176-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

To a solution of methyl 4-methyl-3-oxopentanoate (72 g, 0.5 mol), andethylene glycol (56 g, 1 mol) in toluene (500 mL) was added4-methylbenzenesulfonic acid (1.9 g, 0.01 mol). The mixture was stirredat reflux with a Dean-Stark trap to remove water. The reaction mixturewas washed with a small amount of water and brine, dried over anhydrousNa₂SO₄, and concentrated in vacuum to give the crude methyl2-(2-isopropyl-1,3-dioxolan-2-yl)-acetate (67 g 71% yield), which wasused for the next step without further purification.

Step 2

In a flame-dried three neck flask equipped with an addition funnel,magnetic stirring bar, rubber septum, and a nitrogen inlet, was placedLiAlH₄ (3.12 g, 82.1 mmol) and THF (700 mL). After being cooled at 0°C., a solution of methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)acetate (12 g,63.8 mmol) in THF (160 mL) was added dropwise with stirring. The mixturewas warmed to rt, and stirred for 24 hours. The reaction was quenched byadding water (5 mL), 15% aqueous NaOH (10 mL), and water (5 mL) slowly.The organic layer was separated, and the residue was extracted withEtOAc (3×100 mL). The combined organic phase was dried over Na₂SO₄, andconcentrated to afford the crude product, which was purified by columnchromatography to give 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (6.8 g,67%). ¹H NMR (CDCl₃): δ 0.90 (d, J=6.8 Hz, 6H), 1.87-1.96 (m, 3H), 2.81(br, 1H), 3.69-3.72 (m, 2H), 3.92-4.01 (m, 4H).

Step 3

To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (8.0 g, 50mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH₂Cl₂ (120 mL)was added methanesulfonyl chloride (11.6 mL, 150 mmol) at 0° C., and thereaction mixture was stirred at rt till the reaction was finished. Thereaction mixture was washed with water and brine, dried over Na₂SO₄,filtered, and concentrated to give the crude2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (12 g, crude),which was used for the next step without further purification.

Step 4

To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl methanesulfonate(12 g, 50 mmol) and (S)-1-(4-methoxyphenyl)-ethyl amine (19.9 g, 100mmol) in CH₃CN (250 mL) was added K₂CO₃ (8 g, 58 mmol), and the mixturewas refluxed for 10 h. The solution was filtered, and the filtrate wasconcentrated to afford the crude product, which was purified by columnchromatography to give(S)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl)ethanamine(6.5 g, 38% yield).

Step 5

To a solution of(S)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl)ethanamine(6.5 g, 19 mmol) in MeOH (60 mL) was added conc HCl (60 mL). The mixturewas stirred at 65° C. till the reaction was finished. The mixture wascooled to 0° C., and the pH of the mixture was adjusted to 7 by addingthe satd aq NaHCO₃. The mixture was concentrated, and the residue wasextracted with EtOAc (3×100 mL). The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give(S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (5.5 g, 97%yield), which was used for the next step without further purification.¹H NMR (CDCl₃): δ 1.07 (d, J=6.8 Hz, 6H), 1.29 (d, J=6.4 Hz, 3H), 1.89(br, 1H), 2.54-2.62 (m, 4H), 2.66-2.69 (m, 1H), 3.68-3.72 (m, 1H),7.18-7.20 (m, 2H), 7.41-7.44 (m, 2H).

Step 6

To a suspension of Mg (11 g, 458 mmol) and I₂ (0.5 g) in anhydrous THF(50 mL) was added 3-chloro-2-methylprop-1-ene (1 mL) to initiate thereaction. THF (300 mL) was added, more solution of3-chloro-2-methylprop-1-ene (15 mL) in THF (20 mL) was dropped into thereaction at 0° C. under N₂ over 30 min. A solution of(S)-1-(1-(4-bromophenyl)-ethyl amino)-4-methylpentan-3-one (5 g) in THF(50 mL) was added dropwise at −78° C. over 45 min. The reaction wasstirred at rt for 2 h, cautiously quenched with satd aq NH₄Cl, andfiltered. The filtrate was extracted with EtOAc (3×100 mL), washed withbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to give1-(S-1-(4-bromophenylamino)-3-isopropyl-5-methylhex-5-en-3-ol (6.4 g,90% yield), which was used for the next step without furtherpurification.

Step 7

To a solution of1-(S-1-(4-bromophenylamino)-3-isopropyl-5-methylhex-5-en-3-ol (6.4 g,16.8 mmol) and triethylamine (5.34 g, 52 mmol) in CH₂Cl₂ (260 mL) wasadded triphosgene (2.52 g, 8.5 mmol) at 0° C. under N₂, and the mixturewas stirred at rt overnight. The reaction mixture was quenched withwater, and extracted with CH₂Cl₂ (3×50 mL). The combined organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentrated toafford the crude product, which was purified by column chromatography togive two isomers of3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-one.

Isomer 1: (1.85 g, 27% yield) ¹H NMR (CDCl₃): δ0.83(d, J=7.2 Hz, 3H),0.89 (d, J=7.2 Hz, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.64-1.70 (m, 2H), 1.79(5, 3H), 1.88-1.95 (m, 1H), 2.20-2.34 (m, 2H), 2.59-2.65 (m, 1H),3.01-3.08 (m, 1H), 4.70 (5, 1H), 4.87 (5, 1H), 5.68-5.77 (m, 1H), 7.14(d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H).

Isomer 2: (1.25 g, 18% yield) ¹H NMR (CDCl₃): δ0.87 (d, J=6.8 Hz, 3H),0.92 (d, J=6.8 Hz, 3H), 1.50 (d, J=7.2 Hz, 3H), 1.60-1.66 (m, 1H), 1.78(5, 3H), 1.73-1.79 (m, 1H), 1.78-2.05 (m, 1H), 2.08 (d, J=14.0 Hz, 1H),2.30 (d, J=14.0 Hz, 1H), 2.62-2.68 (m, 1H), 2.98-3.05 (m, 1H), 4.64 (5,1H), 4.84 (5, 1H), 5.70-5.75 (m, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.40 (d,J=8.4 Hz, 2H).

Step 8

To a solution of3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-one.isomer 1(500 mg, 1.32 mmol) in dry CH₂Cl₂ (64 mL) was added m-CPBA (455g, 2.64 mmol) at rt. The reaction mixture was stirred until the startingmaterial was consumed (monitored by TLC). The mixture was diluted with(CH₃)₃COCH₃ (70 mL), washed with 30% Na₂S₂O₃, and aq NaHCO₃ (3×), driedover Na₂SO₄, filtered, and concentrated to give3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-methyloxiran-2-yl)methyl)-1,3-oxazinan-2-oneisomer 1 (520 mg, 99%), which was used directly for the next stepwithout further purification.

Step 9

To a solution of3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-methyloxiran-2-yl)methyl)-1,3-oxazinan-2-oneisomer 1 (520 mg, 1.32 mmol) in THF (32 mL) was added dropwise LiEt₃BH(Super-Hydride, 13.6 mL, 13.6 mmol) at 0° C. under N₂ over 30 min., theresulting solution was stirred at 10-13° C. for 21.5 h. To the mixturewas added H₂O₂ (40 mL). The resulting solution was diluted with(CH₃)₃COCH₃ (380 mL), and washed with water, 30% aq Na₂S₂O₃, and brine.The organic phase was dried over Na₂SO₄, and filtered. The filtrate wasconcentrated to give the crude product, which was purified by columnchromatography to afford3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazinan-2-oneisomer 1 (320 mg, 61%). ¹H NMR (CDCl₃): δ0.82 (d, J=6.8 Hz, 3H), 0.95(d, J=6.8 Hz, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.51 (d, J=10.0 Hz, 3H),1.61 (d, J=15.2 Hz, 1H), 1.78-1.84 (m, 1H), 1.91 (d, J=15.2 Hz, 1H),2.02-2.15 (m, 2H), 2.36 (br, 1H), 2.62-2.68 (m, 1H), 3.03-3.09 (m, 1H),5.73 (t, J=7.2 Hz, 1H), 7.17-7.19 (m, 2H), 7.44-7.48 (m, 2H).

Step 10

To a solution of3((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazinan-2-oneisomer 1 (315 mg, 0.793 mmol) in DMSO (10 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (602mg, 2.38 mmol), CH₃CO₂K (770 mg, 79.3 mmol), Pd(dppf)₂Cl₂ (50 mg, 0.06mmol) under N₂, the reaction was stirred at 90° C. for 4 h. The mixturewas quenched with NH₄Cl, and extracted with EtOAc, washed with water andbrine. The organic phase was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby preparative TLC to give6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (250 mg, 71%).

Step 11

To a solution of6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (250 mg, 0.39 mmol), 4-bromo-1-methylpyridin-2(1H)-one (127 mg,0.68 mmol), Cs₂CO₃ (2N, 4 mL) in 1,4-dioxane (20 mL) was addedPd(PPh₃)₂Cl₂ (54 mg, 0.056 mmol) under N₂. The reaction mixture wasrefluxed for 2 h, quenched with water, and extracted with EtOAc. Theorganic phase was washed with H₂O and brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to give the crude product, whichwas purified by preparative TLC and preparative HPLC to afford6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (79 mg, 47% yield). LC-MS Method 2 t_(R)=1.023 min, m/z=427.6;¹H NMR (CDCl₃) 0.85 (d, 3H), 0.96 (d, 3H), 1.26 (s, 3H), 1.28 (s, 3H),1.54 (m, 4H), 1.84-1.88 (m, 2H), 2.04 (br, 1H), 2.01-2.18 (m, 2H), 2.75(m, 1H), 3.10 (m, 1H), 3.52 (s, 3H), 5.80 (t, 1H), 6.37 (m, 1H), 6.74(m, 1H), 7.28 (m, 1H), 7.25-7.37 (m, 2H), 7.50 (m, 2H).

6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 2 was prepared from3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-oneisomer 2 following procedures analogous to those described in Steps 8-11above. LC-MS Method 2 t_(R)=1.023 min, m/z=427.6; ¹H NMR (CDCl₃) 0.79(d, 3H), 0.92 (d, 3H), 1.27 (s, 3H), 1.30 (s, 3H), 1.51 (d, 3H), 1.58(d, 1H), 1.73-1.81 (m, 1H), 1.88 (d, 1H), 2.0 (br, 1H), 2.04-2.08 (m,2H), 2.65-2.68 (m, 1H), 3.04-3.07 (m, 1H), 3.52 (s, 3H), 5.75 (t, 1H),6.37 (m, 1H), 6.74 (m, 1H), 7.21-7.35 (m, 3H), 7.51 (m, 2H).

EXAMPLE 186-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The two diastereomers of3-((S)-1-(4-bromophenyl)ethyl)-6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-onewere prepared from methyl 3-cyclopropyl-3-oxopropanoate followingprocedures analogous to those described in Example 17 Steps 1-7. Thetitle compound was prepared as follows.

Step 1

To a solution of3-((S)-1-(4-bromophenyl)ethyl)-6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-oneisomer 1 (230 mg, 0.58 mmol) in DMSO (15 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (450mg, 1.77 mmol), CH₃CO₂K (800 mg, 8.16 mmol), Pd(pddf)₂Cl₂ (50 mg, 0.06mmol) under N₂. The reaction was stirred at 90° C. for 34 h, quenchedwith NH₄Cl, and extracted with EtOAc. The organic phase was washed withwater and brine, dried over Na₂SO₄, and filtered. The filtrate wasconcentrated to give the crude product, which was purified bypreparative TLC to give6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (140 mg, 54.3%).

Step 2

To a solution of6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (140 mg, 0.316 mmol), 4-bromo-1-methylpyridin-2(1H)-one (74.3mg, 0.316 mmol), 2 M aq Cs₂CO₃(3 mL) in 1,4-dioxane (20 mL) was addedPd(dppf)₂Cl₂ (30 mg, 0.043 mmol) under N₂. The reaction mixture wasrefluxed for 2 h, quenched with water, and extracted with EtOAc. Theorganic phase was washed with H₂O and brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to give the crude product, whichwas purified by preparative TLC and preparative HPLC to afford6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (49.5 mg, 37.7%). LC-MS Method 2 t_(R)=1.016 min, m/z=367.2; ¹HNMR (CDCl₃) 0.50 (m, 2H), 0.62 (m, 2H), 0.97 (m, 1H), 1.32 (m, 6H), 1.58(d, 3H), 1.97 (m, 3H), 2.28 (m, 1H), 2.78 (m, 1H), 3.40 (m, 1H), 3.58(s, 3H), 5.85 (m, 1H), 6.41 (d, 1H), 6.79 (s, 1H), 7.33 (d, 1H), 7.41(d, 1H), 7.56 (d, 1H)

6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 2 was prepared from3-((S)-1-(4-bromophenyl)ethyl)-6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-oneisomer 2 following procedures analogous to those described in Steps 1and 2 immediately above. LC-MS Method 2 t_(R)=0.99 min, m/z=367.1; ¹HNMR (CDCl₃) 0.02 (m, 3H), 0.23 (m, 1H), 0.51 (m, 1H), 0.96 (s, 6H), 1.17(d, 3H), 1.40-1.60 (m, 4H), 1.94 (m, 1H), 2.55 (m, 1H), 2.73 (m, 1H),3.20 (s, 3H), 5.41 (m, 1H), 6.03 (d, 1H), 6.40 (s, 1H), 6.98 (m, 1H),7.03 (m, 2H), 7.18 (m, 2H)

EXAMPLE 19(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 4

To a solution ofN′-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazide(0.1 g, 0.21 mmol) in THF (2 mL) was added Burgess Reagent (75 mg, 0.315mmol). The sealed vial was irradiated in the microwave at 100° C. for 15min. The mixture was extracted with EtOAc (3×30 mL). The combinedorganic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by preparative TLCto afford(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one(58 mg, yield: 59%). ¹H NMR (CDCl₃): δ1.49-1.51 (m, 3H), 2.23-2.26 (m,2H), 2.30-2.33 (m, 2H), 2.42 (s, 3H), 2.43-2.45 (m, 1H), 2.49-2.54 (m,1H), 2.87-2.91 (m, 1H), 3.06-3.09 (m, 1H), 5.61-5.63 (m, 1H), 6.76-6.78(d, 2H), 7.20-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.37 (m, 3H).

Step 5

To a solution of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one(490 mg, 1.04 mmol), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (424 mg,1.67 mmol) in dry DMSO (20 mL) was added KOAc (326 mg, 3.33 mmol) andPd(dppf)Cl₂ (25.3 mg, 0.031 mmol) under N₂ atmosphere. The mixture waswarmed at 100° C. for 3 h. After TLC showed the starting material haddisappeared, the solid was filtered off, water (50 mL) and EtOAc (50 mL)were added, and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by prep TLC toafford(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(0.395 g, yield: 73.6%).

Step 6

To a solution of(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(60 mg, 0.12 mmol) and 4-iodo-1-methylpyridin-2(1H)-one (33 mg, 0.14mmol) in dry 1,4-dioxane (15 mL) were added Cs₂CO₃ (2M, 1 mL) andPd(PPh₃)Cl₂ (7.7 mg, 0.01 mmol). The mixture was heated at reflux for 2h under N₂ atmosphere, the solid was filtered off, and the mixture wasdiluted with water (30 mL) and EtOAc (30 mL). The combined organiclayers was washed with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by prep TLC to afford(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(25 mg, yield: 41.8%). LC-MS Method 2 t_(R)=0.984 min, m/z=499.1; ¹H NMR(CDCl₃): δ1.48-1.50 (m, 3H), 2.16-2.20 (m, 1H), 2.23-2.26 (m, 1H),2.27-2.32 (m, 2H), 2.39 (s, 3H), 2.40-2.47 (m, 1H), 2.49-2.54 (m, 1H),2.87-2.90 (m, 1H), 2.98-3.01 (m, 1H), 3.58 (s, 3H), 5.62-5.64 (m, 1H),6.45-6.48 (m, 1H), 6.87 (s, 1H), 6.92-6.94 (d, 2H), 7.20-7.24 (m, 4H),7.25-7.35 (m, 4H).

EXAMPLE 20(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To the mixture of 4-iodopyridin-2(1H)-one (50 mg, 0.213 mmol) in DMF (3mL) was added 2-iodoethanol (73 mg, 0.426 mmol), K₂CO₃ (88 mg, 0.638mmol) at rt. The mixture was stirred for 2 h at rt. After the reactionwas finished, the mixture was washed with water and extracted withEtOAc. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated to give the crude product, which was purifiedby TLC to provide 1-(2-hydroxyethyl)-4-iodopyridin-2(1H)-one (60 mg100%).

Step 2

A mixture of compounds(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(72 mg 0.150 mmol), 1-(2-hydroxyethyl)-4-iodopyridin-2(1H)-one (48 mg0.181 mmol), Pd(PPh₃)₂Cl₂ (14 mg, 0.020 mmol), and Cs₂CO₃ (2 mL) in1,4-dioxane (8 mL) was stirred at reflux for 2 h. After the reaction wasfinished, the mixture was washed with water, and extracted with EtOAC.The organic phase was washed with brine, dried over Na₂SO₄, filtered,and concentrated to get the crude product, which was purified by TLC toprovide compound(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(19.7 mg, 28%). LC-MS Method 2 t_(R)=1.065 min, m/z=491.2; ¹H NMR(CDCl₃): δ1.10 (d, 6H), 1.50 (d, 3H), 2.20 (m, 5H), 2.35 (m, 1H), 3.50(m, 1H), 3.90 (m, 2H), 4.10 (m, 2H), 5.60 (m, 1H), 6.40 (m, 1H), 6.70(s, 1H), 6.95 (d, 2H), 7.35 (m, 8H).

EXAMPLE 21(6S)-6-(2,3-dihydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

A solution of 3-chloro-1-phenylpropan-1-one (16.8 g, 0.1 mol) in THF (50mL) was added to a well-stirred suspension of zinc powder (13 g, 0.2mol) in a mixture of satd aq NH₄Cl solution (260 mL) and THF (65 mL). Asolution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2 mol) in THF (50 mL)was added dropwise. The reaction was mildly exothermic, and the mixturebegan to reflux spontaneously. After refluxing had ceased, the mixturewas stirred for 1 h. TLC showed the 3-chloro-1-phenylpropan-1-one hadnot reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g,0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rtovernight. The mixture was extracted with EtOAc (2×500 mL). The combinedorganic layer was dried and concentrated. The residue was purified bycolumn chromatography on silica gel eluted with petroleum ether/EtOAc50:1→30:1→5:1, to give 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (17 g,yield 76%) as an oil. ¹H NMR (CDCl₃): δ1.28 (s, 3H), 2.31 (m, 2H), 2.54(m, 2H), 2.68 (d, 1H), 3.15 (m, 1H), 3.58 (m, 1H), 4.78 (m, 1H), 4.93(m, 1H), 7.27 (t, 1H), 7.38 (m, 4H).

Step 2

A mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (2.9 g, 13 mmol),(S)-1-bromo-4-(1-isocyanatoethyl)benzene (3.5 g, 16 mmol), and DBU (8 g,33 mmol) in THF (80 mL) was heated at reflux overnight. The mixture wasdiluted with EtOAc, and washed with 1 N aq HCl. The aqueous phase wasextracted with EtOAc (3×), and the combined organic phase was dried overNa₂SO₄. After the solvents were evaporated, the crude product waspurified by column chromatography to give(R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(1.62 g, yield: 30%).

Step 3

To a solution of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(300 mg, 0.726 mmol), 4-methylmorpholine 4-oxide (195 mg, 1.44 mmol) ina mixture of H₂O (6 mL), THF (30 mL) and t-BuOH (12 mL) was added osmium(VIII) oxide (4%, 0.231 mL) at 0° C. The mixture was stirred at rtovernight. The mixture was quenched with 3% NaHSO₃ (15 mL×3) andextracted with EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated to give the crude product(S)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(242 mg, 74.5%).

Step 4

To a solution of(S)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(235 mg, 0.524 mmol) in DMSO (5 mL) were added KOAc (771.6 mg, 7.86mmol), Pd(dppf)Cl2 (40 mg) under N2. The mixture was stirred at 90° C.for 3 h. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was dried over Na₂SO₄ and concentrated to givethe crude product, which was purified by preparative TLC to afford(S)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(121 mg, 46.6%).

Step 5

A mixture of(S)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(105 mg, 211.9 mmol), 4-iodo-1-methylpyridin-2(1H)-one (65 mg, 275.5mmol), Pd(PPh₃)₂Cl₂ (20 mg) in aq. Cs₂CO₃ solution (3 mL) was stirred atreflux for 2 h. After the reaction was finished, the mixture was washedwith water and extracted with EtOAc. The organic layer was dried overNa₂SO₄ and concentrated to give the crude product, which was purified bypreparative HPLC to afford two isomers of(6S)-6-(2,3-dihydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Isomer 1 (6.11 mg, 6%): LC-MS Method 2 t_(R)=0.84 min, m/z=477.4; ¹H NMR(CdCl₃): δ 0.97 (s, 3H), 1.55 (d, 3H), 2.27 (m, 3H), 2.38 (m, 3H), 2.91(m, 1H), 3.34 (d, 1H), 3.58 (s, 3H), 5.68 (m, 1H), 6.35 (d, 1H), 6.71(s, 1H), 7.02 (d, 2H), 7.36 (m, 8H).

Isomer 2 (6.78 mg, 6.7%): LC-MS Method 2 t_(R)=0.832 min, m/z=477; ¹HNMR (CDCl₃): δ 1.14 (s, 3H), 1.48 (d, 3H), 2.09 (m, 1H), 2.14 (m, 2H),2.31 (m, 2H), 2.81 (m, 1H), 3.24 (d, 1H), 3.27 (d, 1H), 3.50 (s, 3H),5.62 (m, 1H), 6.28 (d, 1H), 6.63 (s, 1H), 6.98 (d, 2H), 7.27 (m, 8H).

EXAMPLE 22

(6S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

Sodium (90 mg) was added to MeOH (5 mL). When sodium had disappeared, asolution of6(S)-3-(S-1-(4-bromophenyl)ethyl)-6-(2-methyloxiran-2-yl)-methyl)-6-phenyl-1,3-oxazinan-2-one (500 mg, 1.16 mmol) was added to the mixture. The mixturewas stirred at 65° C. for 5 h. The mixture was added H₂O andconcentrated. The residue was extracted with EtOAc, the organic layerwas dried over Na₂SO₄ and concentrated to give the crude product, whichwas purified by preparative TLC (2:1 PE/EtOAc) to afford(S)-3-(S-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(227 mg, 42.3%).

Step 2

To a solution of(S)-3-(S-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(205 mg, 0.443 mmol) in DMSO (5 mL) was added KOAc (435.13 mg, 4.43mmol), Pd(dppf)Cl₂ (45 mg) under N₂. The mixture was stirred at 90° C.for 3 hours. The reaction mixture was quenched by water and extractedwith EtOAc. The organic layer was dried over Na₂SO₄ and concentrated togive the crude product, which was purified by preparative TLC(PE:EA=1:2) to afford(S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(113 mg, 50%).

Step 3

A mixture of(S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(100 mg, 196.29 mmol), 4-iodo-1-methylpyridin-2(1H)-one (60.49 mg, 255.2mmol), Pd(PPh₃)₂Cl₂ (20 mg), and aq Cs₂CO₃ solution (2 mol/L, 3 mL) in1,4-dioxane (4 mL) was stirred at reflux for 2 hours. After the reactionwas finished, the mixture was washed with water and extracted withEtOAc. The organic layer was dried over Na₂SO₄ and concentrated to givethe crude product, which was purified by preparative HPLC to afford twoisomers of(6S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one.

Isomer 1 (5.25 mg, 5.6%): LC-MS Method 2 t_(R)=0.921 min, m/z=403.2; ¹HNMR (CDCl₃): δ 0.94 (s, 3H), 1.47 (d, 3H), 2.28 (m, 4H), 2.35 (m, 1H),2.82 (m, 1H), 3.11 (d, 1H), 3.16 (s, 3H), 3.25 (d, 1H), 3.50 (s, 3H),5.62 (m, 1H), 6.27 (d, 1H), 6.63 (s, 1H), 6.92 (d, 2H), 7.25 (m, 8H).

Isomer 2 (5.40 mg, 5.8%): LC-MS Method 2 t_(R)=0.923 min, m/z=513.1; ¹HNMR (CDCl₃): δ 1.18 (s, 3H), 1.47 (d, 3H), 2.11 (m, 2H), 2.23 (m, 2H),2.45 (m, 1H), 2.81 (d, 2H), 2.96 (d, 1H), 3.15 (s, 3H), 3.50 (s, 3H),5.62 (m, 1H), 6.27 (d, 1H), 6.65 (s, 1H), 6.90 (d, 2H), 7.26 (m, 8H).

EXAMPLE 23(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

To a solution of 2-fluorobenzoyl chloride (50 g, 0.31 mol) in CH₂Cl₂(200 mL) was added N,O-dimethylhydroxylamine (46 g, 0.47 mol), and asolution of triethylamine (127 g, 1.26 mol) in CH₂Cl₂ (100 mL) at 0° C.The reaction mixture was warmed slowly to rt, and stirred for 3 h. Themixture was quenched with iced water and extracted with CH₂Cl₂ (200 mL).The organic layer was dried over Na₂SO₄, filtered, and concentrated toafford 2-fluoro-N-methoxy-N-methylbenzamide (48 g, yield: 84.6%).

Step 2

A solution of 2-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4 mmol) inTHF (150 mL) was cooled to −78° C. Vinylmagnesium bromide (120 mL, 120mmol) was slowly added, and the mixture stirred at −78° C. for 10 min,slowly warmed to rt, and stirred for another 3 h. The reaction mixturewas quenched with 1 N aq HCl (100 mL) at 0° C. The aqueous layer wasextracted with EtOAc (100 mL). The combined organic phase was washedwith brine (50 mL), dried over Na₂SO₄, and concentrated. The residue waspurified by column chromatography to afford1-(2-fluorophenyl)-prop-2-en-1-one (7.6 g, yield: 58.4%) as a colorlessoil.

Step 3

To a solution of 1-(2-fluorophenyl)-prop-2-en-1-one (5.6 g, 37.3 mmol)in CH₃CN (50 mL) was added (S)-1-(4-bromophenyl)-ethylamine (7.4 g, 37mmol), and the mixture was stirred for 12 h at 40° C. The solution wasconcentrated to afford the crude product, which was purified by columnchromatography to give(S)-3-(1-(4-bromophenyl)-ethylamino)-1-(2-fluorophenyl)-propan-1-one (4g, yield: 30.7%) as a yellow liquid.

Step 4

To a suspension of Mg (2.5 g, 104 mmol), I₂(0.1 g) in anhydrous THF (15mL) was added 3-chloro-2-methylprop-1-ene (0.6 mL, 6 mmol). After asolution of 3-chloro-2-methylprop-1-ene (9 mL, 90 mmol) in THF (120 mL)was dropped at 0° C. under N₂ in 30 min.(S)-3-(1-(4-bromophenyl)-ethylamino)-1-(2-fluorophenyl)-propan-1-one (3g, 8.6 mmol) in THF (50 mL) was added dropwise at −78° C. over 45 min.The reaction mixture was stirred at rt for 2 h and cautiously quenchedby addition of satd aq NH₄Cl. The mixture was extracted with EtOAc, andthe organic layer was washed with brine, dried over anhydrous Na₂SO₄,and concentrated in vacuo to give1-(S-1-(4-bromophenyl)-ethylamino)-3-(2-fluorophenyl)-5-methylhex-5-en-3-ol(3.3 g, yield: 94.5%), which was used for the next step without furtherpurification.

Step 5

A mixture of1-(5-1-(4-bromophenyl)ethylamino)-3-(2-fluorophenyl)-5-methylhex-5-en-3-ol(2 g, 5 mmol) in a solution of triethylamine (1.5 g, 15 mmol) in1,2-dichloroethane (100 mL) was added triphosgene (1.46 g, 5 mmol) at 0°C. under N₂, and the mixture was heated at 100° C. for 4 h. The reactionmixture was quenched with water, and extracted with CH₂Cl₂ (100 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated to afford the crude product (2.1 g, yield:99%), which was used for the next step without further purification.

Step 6

To a solution of(S)-3-(1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-6-(2-methylallyl)-1,3-oxazinan-2-one(3.2 g, 7.4 mmol) in dry CH₂Cl₂ (100 mL) was added m-CPBA (2.6 g, 14.8mmol) at rt and the mixture was stirred overnight. The mixture wasdiluted with (CH₃)₃COCH₃ (100 mL), washed with 30% aq Na₂S₂O₃ and aqNaHCO₃, dried over Na₂SO₄, filtered, and concentrated to give3-(S-1-(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-(2-methyloxiran-2-yl-methyl)-1,3-oxazinan-2-one(2.8 g, yield: 84.3%), which was used directly for the next step withoutfurther purification.

Step 7

To a solution of3-(S-1-(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-(2-methyloxiran-2-yl)-methyl)-1,3-oxazinan-2-one(2.2 g, 4.92 mmol) in THF (100 mL) was added dropwise LIEt₃BH(Super-hydride, 50 mL, 50 mmol) at 0° C. under N₂ for 30 min., and theresulting mixture was stirred at 2-3° C. for 1.5 h, and stirred for 2.5h at 10-13° C. H₂O₂ (20 mL) was added dropwise and the reaction mixturewas diluted with (CH₃)₃COCH₃ (280 mL). The mixture was washed withwater, 30% aq Na₂S₂O₃ and brine. The organic phase was dried over Na₂SO₄and filtered. The filtrate was concentrated to give the crude product,which was purified by column chromatography to afford(S)-3-(S-1-(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one(550 mg, 23.9%) as a white solid. ¹H NMR (CDCl₃): δ 1.03 (s, 3H), 1.14(s, 3H), 1.43 (d, J=6.8 Hz, 3H), 2.08-2.13 (m, 1H), 2.17 (d, J=2.8 Hz,1H), 2.21-2.22 (m, 1H), 2.31 (dd, J=0.8, 15.2 Hz, 1H), 2.77-2.81 (m,1H), 5.56 (q, J=2.8 Hz, 2H), 6.82-6.83 (m, 2H), 6.85-6.94 (m, 1H),7.08-7.13 (m, 1H), 7.18-7.25 (m, 1H), 7.26-7.40 (m, 2H), 7.42-7.44 (m,1H).

Step 8

To a solution of(S)-3-(S-1-(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one(540 mg, 1.2 mmol) in DMSO (15 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (900mg, 3.3 mmol), CH₃CO₂K (1.5 g, 16 mmol), Pd(dppf)Cl₂ (108 mg, 0.13 mmol)under N₂, and the reaction was stirred at 90° C. for 2.5 h. The mixturewas quenched with water, and extracted with EtOAc (90 mL). The organiclayer was washed with water and brine, dried over Na₂SO₄, and filtered.The filtrate was concentrated to give the crude product, which waspurified by preparative TLC to afford(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(360 mg, 62%) as a yellow liquid.

Step 9

To a solution of(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(120 mg, 0.24 mmol), 5-bromo-1-methylpyridin-2-(1H)-one (54 mg, 0.28mmo), 2N aq Cs₂CO₃ (2 mL) in dioxane (8 mL) was added Pd(PPh₃)₂Cl₂ (17mg, 0.024 mmol) under N₂. The reaction mixture was refluxed for 2 h andquenched by addition of water. The mixture was extracted with EtOAc (30mL), and the organic layer was washed with H₂O and brine, dried overNa₂SO₄, and filtered. The filtrate was concentrated to give the crudeproduct, which was purified by preparative TLC and preparative HPLC toafford(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(14 mg, yield: 10%). LC-MS Method 2 t_(R)=1.2 min, m/z=473.9; ¹H NMR(CDCl₃): δ1.21 (5, 3H), 1.30 (5, 3H), 1.48 (d, J=7.2 Hz, 3H), 2.15-2.26(m, 3H), 2.33 (dd, J=11.2, 26.4 Hz, 1H), 2.43-2.46 (m, 1H), 2.79-2.85(m, 1H), 3.63 (s, 3H), 5.62 (q, J=6.8 Hz, 1H), 6.58-6.60 (m, 1H),6.89-6.94 (m, 1H), 7.00-7.02 (m, 2H), 7.10-7.24 (m, 3H), 7.34-7.39 (m,1H), 7.40-7.45 (m, 1H), 7.48-7.70 (m, 2H).

EXAMPLE 24(S)-6-(3-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-(1-(4-bromophenyl)ethylamino)-1-(3-fluorophenyl)propan-1-onefollowing procedures analogous to those described in Steps 4-9 inExample 23. LC-MS Method 2 t_(R)=1.416 min, m/z=500.9; ¹H NMR (CDCl₃)1.18 (s, 3H), 1.29 (s, 3H), 1.47 (d, 3H), 2.05-2.28 (m, 4H), 2.31-2.39(m, 1H), 2.82-2.87 (m, 1H), 3.58 (s, 3H), 5.64 (q, 1H), 6.57-6.59 (m,1H), 6.88-7.19 (m, 5H), 7.21-7.25 (m, 2H), 7.28 (m, 1H), 7.36 (m, 1H),7.40-7.45 (m, 1H), 7.45-7.48 (m, 1H)

(S)-3-(1-(4-bromophenyl)ethylamino)-1-(3-fluorophenyl)propan-1-one wasprepared as shown below.

Step 1

A solution of 3-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4 mmol) inTHF (150 mL) was cooled to −78° C. Vinylmagnesium bromide (120 mL, 120mmol) was added slowly. The mixture was stirred at −78° C. for 10 min,at rt for 3 h, and quenched by addition of 1 N aq HCl (100 mL) at 0° C.The aqueous layer was extracted with EtOAc (100 mL). The combinedorganic phase was washed with brine (50 mL), dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography toafford 1-(3-fluorophenyl)ethanone (9.7 g, yield: 75%) as a colorlessoil.

Step 2

1-(3-Fluorophenyl)ethanone (17 g, 0.123 mol), dimethylamine (13.7 g,0.172 mol), and paraformaldephyde (5.5 g, 0.185 mol) were suspended inethanol (50 mL), and conc HCl solution (0.3 mL) was added. The mixturewas heated at reflux overnight. The solvent was removed under vacuum,and the residue was washed with EtOAc (3×) to give3-(dimethylamino)-1-(3-fluorophenyl)propan-1-one (20.7 g, 88%), whichwas used for the next step without purification.

Step 3

A solution of 3-dimethylamino-1-(3-fluoro-phenyl)-propan-1-one (17 g,0.087 mol) and (S)-1-(4-bromophenyl)-ethanamine (17 g, 0.087 mol) in amixture of EtOH (50 mL) and H₂O (50 mL) was refluxed at 80° C.overnight. The solvent was removed under vacuum, and the residue waspurified by column chromatography to afford(S)-3-(1-(4-bromophenyl)-ethylamino)-1-(3-fluorophenyl)-propan-1-one(6.2 g, 20%).

EXAMPLE 25(S)-3-((S)-1-(4-(1-(2-fluoroethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

1-(2-fluoroethyl)-4-iodopyridin-2(1H)-one was prepared from4-iodopyridin-2(1H)-one and 2-fluoroethyl trifluoromethanesulfonatefollowing a procedure analogous to that described in Example 20 Step 1.

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 1-(2-fluoroethyl)-4-iodopyridin-2(1H)-one following a procedureanalogous to that described in Example 6 Step 1. LC-MS Method 2t_(R)=1.09 min, m/z=515, 493, 475, 435.

EXAMPLE 26(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 23 Step 9. LC-MS Method 2 t_(R)=1.58 min,m/z=501, 479, 421.

EXAMPLE 27(S)-6-(3-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(3-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 23 Step 9. LC-MS Method 2 t_(R)=1.57 min,m/z=501, 479, 421.

EXAMPLE 286-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

To a mixture of3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one(100 mg, 0.26 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (198 mg,0.783 mmol), potassium acetate (256 mg, 2.61 mmol) in DMSO (5 mL) wasadded Pd(dppf)Cl₂ (21 mg, 0.0261 mmol) under N₂. The mixture was stirredat 85° C. for 3 h, treated with EtOAc (50 mL) and water (50 mL). Theorganic layer was washed with water (2×50 mL) and brine (50 mL), dried,and concentrated to give the crude product. The crude product waspurified by preparative TLC to give6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(40 mg, 35%),

Step 2

A mixture of6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(40 mg, 0.092 mmol), 4-iodo-1-methylpyridin-2(1H)-one (20 mg, 0.085mmol), Pd(PPh₃)₂Cl₂ (6 mg, 0.0085 mmol), and Cs₂CO₃ (2 N, 0.425 mL, 0.85mmol) in 1,4-dioxane (2 mL) was refluxed for 3 h under N₂. The reactionmixture was treated with EtOAc (20 mL) and water (20 mL), and theorganic layer was dried and concentrated in vacuo. The residue waspurified by preparative HPLC to give two isomers.

Isomer 1: (2.20 mg, 6%). LC-MS Method 2 t_(R)=1.06 min, m/z=413; m/z=¹HNMR (CD₃OD): δ 1.00 (m, 6H), 1.62 (m, 7H), 1.82 (m, 1H), 2.10 (m, 2H),2.85 (m, 1H), 3.29 (m, 1H), 3.54 (t, 2H), 3.63 (s, 3H), 5.71 (q, 1H),6.78 (dd, 1H), 6.83 (d, 1H), 7.51 (d, 2H), 7.75 (m, 3H),

Isomer 2: (2.10 mg, 6%) LC-MS Method 2 t_(R)=1.03 min, m/z=413; ¹H NMR(CD₃OD): δ 0.86 (m, 6H), 1.53 (m, 5H), 1.71 (m, 4H), 1.92 (m, 1H), 2.82(m, 1H), 3.25 (m, 1H), 3.49 (t, 2H), 3.52 (s, 3H), 5.59 (q, 1H), 6.67(dd, 1H), 6.72 (d, 1H), 7.39 (d, 2H), 7.63 (m, 3H),

EXAMPLE 29(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

A mixture of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(150 mg, 0.375 mmol) and 6-aminopyridin-3-ylboronic acid (56 mg, 0.45mmol), Pd(Ph₃P)₂Cl₂ (15 mg), and aqueous Cs₂CO₃ solution (0.5 mL, 2 M)in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. Theorganic phase was separated, and concentrated to give the crude product,which was purified by preparative HPLC to give(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(90 mg, 60%).

Step 2

To a solution of(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(90 mg, 0.23 mmol) in tetrahydrofuran (10 mL) was added BH₃ THF (3.0 mL,1 mol/L, 4 mmol) at 0° C. under nitrogen atmosphere. The formed mixturewas stirred for 2 h. The reaction was quenched by water. Then NaOH (2mL, 3 mol/L) and H₂O₂ (1 mL) was added to the above mixture. When thereaction was over, the mixture was extracted with EtOAc. The combinedorganic phase was concentrated to give the crude product, which waspurified by preparative HPLC to give(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 41%).

Step 3

(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(40 mg, 0.09 mmol.) was dissolved in 3.5 M H₂SO₄ (10 mL), and 2 M NaNO₂(10 mL) was added at 0° C. The reaction mixture was stirred at rt for 2h and treated with NaOH solution. The mixture was extracted with EtOAc.The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated to afford the residue, which was purified bypreparative HPLC to give(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(10 mg, 20%). LC-MS Method 2 t_(R)=1.66, min, m/z=433, 455; ¹H NMR(CDCl₃): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H),2.10-2.30 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.12 (m, 1H), 6.62 (m,1H), 6.86 (m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1H), 7.62(m, 1H).

EXAMPLE 30(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a suspension of NaH (4.8 g, 0.2 mol) in THF (10 mL) was added asolution of 5-bromopyridin-2(1H)-one (8.6 g, 0.05 mol) in THF (120 mL)at 0° C. The resulting mixture was stirred for 1 h and CH₃I (35.5 g,0.25 mol) was added. The mixture was stirred for 3 h. The reaction wasquenched with aqueous NH₄Cl solution. The organic phase was concentratedto give the crude product, which was purified by column chromatographyto give 5-bromo-1-methylpyridin-2(1H)-one (8.9 g, 96.78%). ¹H NMR(CDCl₃): δ=3.5 (S, 3H), 6.52 (m, 1H), 7.32 (m, 1H), 7.45 (m, 1H).

Step 2

A mixture of(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(1.7 g, 3.7 mmol) and 5-bromo-1-methylpyridin-2(1H)-one (816 mg, 4.4mmol), Pd(Ph₃P)₂Cl₂ (200 mg), and aq Cs₂CO₃ solution (4 mL, 2M) in1,4-dioxane (30 mL) was stirred and heated to reflux for 2 h. When thereaction was over, the mixture was washed with water and extracted withEtOAc, and the organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated to give crude product, which was purified bypreparative TLC to give(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(614 mg, 37%). LC-MS Method 2 t_(R)=1.075 min, m/z=447.1; ¹H NMR(CDCl₃): δ=1.38 (m, 1H), 1.47 (d, 3H), 1.73 (m, 2H), 1.98 (m, 2H), 2.20(m, 1H), 2.31 (m, 2H), 2.94 (m, 1H), 3.51 (m, 2H), 3.56 (s, 3H), 5.63(m, 1H), 6.67 (m, 1H), 6.87 (m, 2H), 7.05 (m, 2H), 7.31-7.41 (m, 6H),7.48 (m, 1H).

EXAMPLE 31(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

To a solution of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(0.064 g, 0.144 mmol, 1.0 equiv) in THF—H₂O (1:1, 6 mL) were added NaIO₄(0.145 g, 0.678 mmol, 4.7 equiv) and OsO₄ (2.5 wt. % solution in t-BuOH,0.048 g, 0.0047 mmol, 0.033 equiv), and the mixture was stirred at rtfor 1 h. The mixture was diluted with EtOAc, dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was dissolved in MeOH(3 mL) and NaBH₄ (0.100 g) was added. After the mixture was stirred for0.5 h at rt, acetone was added. The solvents were removed in vacuo, theresidue was treated with saturated brine, extracted with CH₂Cl₂, anddried over Na₂SO₄. After the solvent was evaporated, the residue waspurified by reversed-phase HPLC (SunFire™ Prep O₁₈ OBD™ 5 μm 19×50 mmcolumn, 10%→90% CH₃CN/H₂O, 0.1% CF₃COOH over 8 min and then 90%CH₃CN/H₂O, 0.1% CF₃COOH over 2 min, flow rate 20 mL/min) to afford(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-(S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one.LC-MS Method 1 t_(R)=1.21 min, m/z=451 (M+1); ¹H NMR (400 MHz, CD₃OD) δ7.80 (m, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.22-7.19 (m, 4H), 7.00-6.92 (m,4H), 6.52 (d, J=9.4 Hz, 1H), 5.45 (q, J=7.0 Hz, 1H), 3.60-3.52 (m, 1H),3.52 (s, 3H), 3.24-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.39-2.35 (m, 1H),2.23-2.12 (m, 2H), 2.01 (t, J=7.3 Hz, 2H), 1.43 (d, J=7.0 Hz, 3H); ¹⁹FNMR (376 MHz, CD₃OD) δ −117.19 (m).

EXAMPLE 32(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Method 1

Step 1

A mixture of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.6 g, 3.84 mmol) and 6-aminopyridin-3-ylboronic acid (1.0g, 4.61 mmol), Pd(Ph₃P)₂Cl₂ (150 mg), and aq Cs₂CO₃ solution (3.84 mL, 2M) in 1,4-dioxane (150 mL) was stirred and heated to reflux for 2 h. Themixture was filtered and the filtrate was extracted with EtOAc. Thecombined organic phase was washed with brine, dried over anhydrousNa₂SO₄, and concentrated to give(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(1.5 g, 90%), which was used for the next step without purification. ¹HNMR (CDCl₃): δ=1.51 (d, 3H), 2.17-2.31 (m, 3H), 2.54-2.60 (m, 2H), 2.90(m, 1H), 4.46 (s, 2H), 4.99-5.09 (m, 2H), 5.65-5.71 (m, 2H), 6.54 (m,2H), 6.88 (d, 2H), 7.03 (t, 2H), 7.21-7.27 (m, 3H), 7.58 (d, 1H), 8.22(d, 1H).

Step 2

To a solution of(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(1.5 g, 3.47 mmol.) in 3.5 M H₂SO₄ (25 mL) was added 2 M NaNO₂ (15 mL)at 0° C. The reaction mixture was stirred at rt overnight. The reactionwas treated with aqueous NaOH solution (8%), and the mixture wasextracted with CH₂Cl₂. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated to give crude product,which was purified by preparative TLC to give(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(891 mg, 59%). ¹H NMR (CDCl₃): δ=1.52 (d, 3H), 2.15-2.38 (m, 3H),2.51-2.60 (m, 2H), 2.94 (m, 1H), 4.99-5.11 (m, 2H), 5.65-5.74 (m, 2H),6.67 (m, 1H), 6.89 (d, 2H), 7.00 (t, 2H), 7.13-7.20 (m, 2H), 7.20-7.27(d, 2H), 7.33 (m, 1H), 7.46 (m, 1H), 7.77 (m, 1H).

Step 3

To a suspension of NaH (330 mg, 8.24 mmol) in THF (20 mL) was added asolution of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(891 mg, 0.174 mmol) in THF (30 mL) at 0° C., and the resulting mixturewas stirred for 1 h. CH₃I (2 ml) was added and the mixture was stirredovernight. The reaction was quenched by aqueous NH₄Cl solution. Theorganic phase was separated, and concentrated to give the crude product,which was purified by preparative TLC to give(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(634 mg, 69%). ¹H NMR (CDCl₃): δ=1.52 (d, 3H), 2.16-2.35 (m, 3H),2.52-2.64 (m, 2H), 2.94 (m, 1H), 3.61 (s, 3H), 5.00-5.11 (m, 2H),5.66-5.74 (m, 2H), 6.64 (d, 1H), 6.90 (d, 2H), 7.02 (t, 2H), 7.11-7.14(d, 2H), 7.25-7.28 (m, 2H), 7.41 (m, 1H), 7.53 (m, 1H).

Step 4

To a solution of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(320 mg, 0.717 mmol) in acetone (20 mL) was added aqueous KMnO₄ andNaIO₄ solution (15 mL). Then the formed mixture was stirred for 30 minat 0° C. The mixture was filtered, and the filtrate was adjusted topH=5-6 with 1 N aq HCl solution. The mixture was extracted with EtOAc,and the combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated to give2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)aceticacid.

Step 5

To a solution of2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)aceticacid (290 mg, 0.625 mol) in MeOH (20 mL) was added SOCl₂ (2 mL) at 0°C., and the reaction mixture was stirred at rt for 2 h. The reactionmixture was concentrated to give the residue, which was purified bypreparative TLC to give methyl2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate(130 mg, 43.5%). ¹H NMR (CDCl₃): δ=1.52 (d, 3H), 2.36-2.55 (m, 3H),2.67-2.71 (m, 2H), 2.90-3.04 (m, 3H), 3.68 (s, 3H), 3.71 (s, 3H), 5.66(m, 2H), 6.66 (d, 1H), 6.90 (d, 2H), 7.03 (t, 2H), 7.13-7.15 (d, 2H),7.23-7.29 (m, 2H), 7.42 (m, 1H), 7.56 (m, 1H).

Step 6

To a solution of methyl2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate(130 mg, 0.22 mmol) in dry THF (20 mL) was added MeMgBr (2 mL) at −78°C., and the mixture was stirred under N₂ at rt overnight. The reactionwas quenched with water, and the mixture was extracted with EtOAc. Thecombined organic phase was dried over Na₂SO₄, and concentrated to givethe residue, which was purified by preparative HPLC to give(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(24 mg, 30%). LC-MS Method 2 t_(R)=1.116 min, m/z=479.1; ¹H NMR (CDCl₃):1.1 (m, 6H), 1.18 (m, 1H), 1.48 (d, 3H), 1.58 (m, 1H), 1.80-2.00 (m,2H), 2.21 (m, 3H), 2.86 (m, 1H), 5.55 (m, 1H), 7.72 (m, 2H), 7.00 (m,2H), 7.18 (m, 4H).

Method 2

Step 1

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(5 g, 12 mmol) and CuCl (2.75 g, 27.8 mmol) in dry DMF (50 mL) was addedH₂O (20 mL) and PdCl₂ (950 mg, 3.2 mmol) at room temperature. Themixture was vigorously stirred under a balloon of oxygen for 24 h. AfterTLC showed the starting material had disappeared, the solid was filteredoff. Water (200 mL) and EtOAc (50 mL) was added, the layers wereseparated and the aqueous layer was extracted with EtOAc (3×40 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one(5.25 g, 92%), which was purified by column chromatography. ¹H NMR(CDCl₃): 1.47 (s, 3H), 2.06 (s, 3H), 2.10-2.36 (m, 3H), 2.58 (m, 1H),2.90 (m, 2H), 5.58 (m, 1H), 6.69 (m, 1H), 6.79 (m, 1H), 7.02 (m, 2H),7.19-7.33 (m, 4H).

Step 2

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one(5.25 g, 12.1 mmol) in anhydrous THF (100 mL) was added dropwisemethylmagnesium bromide (20 mL, 60 mmol) at −78° C. under nitrogen. Thenthe mixture was stirred at rt for 2 h. The reaction mixture was cooledin an ice bath and quenched with aqueous NH₄Cl. The layers wereseparated. The aqueous layer was extracted with EtOAc (15 mL), washedwith a brine (30 mL), dried over Na₂SO₄ and concentrated in vacuo togive the crude product, which was purified by preparative HPLC andchiral HPLC to afford(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one(2.5 mg, 46%). ¹H NMR (CDCl₃): 1.08 (s, 3H), 1.12 (s, 3H), 1.48 (m, 3H),1.99 (m, 1H), 2.10-2.24 (m, 4H), 2.35 (m, 1H), 2.85 (m, 1H), 5.61 (m,1H), 6.80 (m, 2H), 6.99 (m, 2H), 7.15-7.28 (m, 5H).

Step 3

A mixture of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one(640 mg, 1.42 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (470 mg,1.85 mmol), PdCl₂dppf (40 mg, 0.047 mmol, KOAc (490 mg, 4.97 mmol) inDMSO (8 mL) was heated at 90° C. for 20 h. The mixture was diluted withEtOAc, and washed with water. The organic phase was separated, andconcentrated to give the crude product, which was purified bypreparative TLC to afford(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(700 mg, 99%). ¹H NMR (CDCl₃): δ=1.08 (s, 3H), 1.13 (s, 3H), 1.32 (s,12H), 1.51 (t, 3H), 1.94 (m, 2H), 2.16 (m, 5H), 2.33 (m, 1H), 2.83 (m,1H), 5.69 (m, 1H), 6.99 (m, 4H), 7.25 (m, 2H), 7.61 (m, 2H).

Step 4

A mixture of(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(700 mg, 1.41 mmol), 5-bromo-1-methylpyridin-2(1H)-one (398 mg, 2.12mmol), PdCl₂(Ph₃P)₂ (70 mg), Cs₂CO₃ (1.5 mL, 3.0 mmol) in 1,4-dioxane(15 mL) was heated under reflux for 2 h. The mixture was diluted withEtOAc, and washed with water. The organic phase was separated, andconcentrated to give the crude product, which was purified bypreparative TLC to afford(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(150 mg, 22%). ¹H NMR (CDCl₃): δ=1.12 (s, 3H), 1.13 (s, 3H), 1.51 (t,3H), 2.16 (m, 2H), 2.21 (m, 2H), 2.41 (m, 1H), 2.92 (m, 1H), 3.63 (s,3H), 5.69 (q, 1H), 6.69 (m, 1H), 6.99 (m, 4H), 7.18 (m, 2H) δ 7.27 (m,2H) δ 7.42 (m, 1H), 7.52 (m, 1H).

EXAMPLE 33(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(1.19 g, 2.8 mmol) in THF (30 mL) was added BH₃ THF (8.5 mL, 1 mol/L,8.5 mmol) at 0° C. under nitrogen atmosphere. The formed mixture wasstirred for 2 h. The reaction was quenched with water. Then NaOH (1mol/L, 6 mL) and H₂O₂ (5 mL) were added to the above mixture. When thereaction was over, the mixture was extracted with EtOAc. The combinedorganic phase was concentrated to give the crude product, which waspurified by preparative TLC to give(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one(1.13 g, 92%).

Step 2

A mixture of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one(520 mg, 1.2 mmol) and 6-aminopyridin-3-ylboronic acid (280 mg, 1.44mmol), Pd(Ph₃P)₂Cl₂ (100 mg), and aq Cs₂CO₃ solution (3 mL, 2M) in1,4-dioxane (20 mL) was stirred and heated to reflux for 2 h. Theorganic phase was separated, and concentrated to give crude product,which was purified by preparative TLC to give(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluoophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one. (400 mg, 74%).

Step 3

(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one(400 mg, 0.88 mmol.) was dissolved in 3.5 M H₂SO₄ (10 mL), and 2 M NaNO₂(6 mL) was added at 0° C. The reaction mixture was stirred at rt for 20min. The reaction mixture was then treated with aqueous NaOH solution(8%), and extracted with CH₂Cl₂. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated to give crudeproduct, which was purified by preparative TLC to give(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(350 mg, 0.78 mmol). ¹H NMR (CDCl₃): δ=1.10-1.25 (m, 8H), 1.37 (m, 1H),1.42-1.55 (m, 2H), 1.78-1.93 (m, 2H), 2.10-2.38 (m, 2H), 2.87 (m, 2H),3.52-3.58 (m, 1H), 3.31-3.97 (m, 1H), 4.12-4.19 (m, 1H), 5.53-5.63 (m,1H), 6.85-7.15 (m, 3H), 7.35-7.55 (m, 1H), 7.75-7.89 (m, 1H), 8.10-8.12(m, 1H).

Step 4

A mixture of(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(100 mg, 0.78 mmol), imidazole (142.8 mg, 2.1 mmol), andtert-butylchlorodimethylsilane (350 mg, 2.34 mmol) in CH₂Cl₂ (20 mL) wasstirred overnight. The mixture was washed with water and extracted withEtOAc. The combined organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated to give crude(R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(120 mg), which was used for the next step without further purification.

Step 5

To a suspension of NaH (18 mg, 0.72 mmol) in THF (0.5 mL) was added asolution of(R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(100 mg, 0.18 mmol) in THF (10 mL) at 0° C. The resulting mixture wasstirred for 1 h. Then CH₃I (613 mg, 43.2 mmol) was added, and themixture was stirred for 3 h. The reaction was quenched with aq NH₄Clsolution. The organic phase was separated, and concentrated to give(R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(104 mg, 100%), which was used for the next step without furtherpurification.

Step 6

A mixture of(R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(200 mg, 0.35 mmol) and TBAF (182 mg, 0.7 mmol) in CH₃CN was stirred andheated to reflux for 15 min. When the reaction was over, the mixture waswashed with water and extracted with EtOAc. The combined organic phasewas washed with brine, dried over Na₂SO₄, filtered and concentrated togive crude product, which was purified by preparative HPLC to give(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(5.01 mg, 4%). LC-MS Method 2 t_(R)=1.065 min, m/z=464.21; ¹H NMR(CDCl₃): δ=1.38 (m, 1H), 1.47 (d, 3H), 1.63 (m, 2H), 1.91 (m, 2H),2.10-2.30 (m, 3H), 2.87 (m, 1H), 2.84 (m, 1H), 3.51 (m, 2H), 3.56 (s,3H), 5.63 (m, 1H), 6.67 (m, 1H), 6.87-6.98 (m, 4H), 7.15 (m, 2H), 7.27(m, 1H), 7.29 (m, 1H), 7.32 (m, 1H), 7.55 (m, 1H).

EXAMPLE 34N-(3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneby treatment with (i) MeSO₂Cl and (ii) MeSO₂NH₂. LC-MS Method 2t_(R)=1.02 min, m/z=542.3; ¹H NMR (CDCl₃) 1.35 (m, 1H), 1.53 (d, 3H),1.69 (m, 1H), 1.89 (m, 1H), 2.00 (m, 1H), 2.17-2.33 (m, 3H), 2.89 (s,3H), 2.97 (m, 1H), 3.06 (m, 2H), 3.66 (s, 3H), 4.38 (s, 1H), 5.67 (m,1H), 6.82 (d, 1H), 6.99 (m, 4H), 7.15 (m, 2H), 7.22 (m, 2H), 7.47 (s,1H), 7.63 (d, 1H).

EXAMPLE 353-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamidefollowing procedures analogous to those described in Example 33 Steps 2and 3. LC-MS Method 2 t_(R)=0.999 min, m/z=446.1; ¹H NMR (CD₃OD) 1.53(d, 3H), 1.91-2.01 (m, 1H), 2.18-2.34 (m, 4H), 2.35-2.51 (m, 2H),3.03-3.12 (m, 1H), 5.56 (m, 1H), 6.62 (d, 2H), 7.03 (d, 2H), 7.24-7.44(m, 7H), 7.59 (m, 1H), 7.87 (m, 1H).

EXAMPLE 36(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-oneusing a procedure analogous to that described in Example 33 Steps 2 to6. LC-MS Method 2 t_(R)=1.038 min, m/z=433.1; ¹H NMR (CDCl₃) 1.48 (d,3H), 2.06-2.19 (m, 2H), 2.11-2.31 (m, 3H), 2.84 (m, 1H), 3.50 (m, 1H),3.54 (s, 3H), 3.72 (m, 1H), 5.62 (m, 1H), 6.60 (d, 1H), 6.86 (d, 2H),7.06 (d, 2H), 7.26 (m, 3H), 7.32 (m, 3H), 7.47 (d, 1H).

EXAMPLE 37(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Method 1

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneusing procedures analogous to those described in Example 33 Steps 2, 3and 5, followed by procedures analogous to those described inPreparation 1 Method 1 Steps 4 and 6. LC-MS Method 2 t_(R)=1.116 min,m/z=461.1; ¹H NMR (CDCl₃) 1.09 (s, 3H), 1.16 (s, 3H), 1.51 (m, 3H),2.05-2.20 (4H), 2.40 (m, 1H), 2.84 (m, 1H), 3.59 (s, 3H), 5.64 (m, 1H),6.62 (m, 1H), 6.96 (m, 2H), 7.14 (m, 2H), 7.28-7.39 (m, 5H), 7.48 (m,1H), 7.50 (m, 1H).

Method 2

Step 1

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(20 g, 50 mmol) and CuCl (12.4 g, 125 mmol) in dry DMF (50 mL) was addedH₂O (12 mL) and PdCl₂ (2.66 g, 15 mmol) at 0˜−5° C. After addition, themixture was allowed to warm to rt gradually for 48 h under O₂. After TLCshowing the stating material had disappeared, the solid was filteredoff. Water (200 mL) and EtOAc (50 mL) were added. The layers wereseparated and the aqueous layer was extracted with EtOAc (3×40 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give a residue, which was purified bycolumn chromatography to give(S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one(12 g, 58%).

Step 2

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one(12 g, 28.8 mmol) in anhydrous THF (100 mL) was added dropwisemethylmagnesium bromide (48 mL, 144 mmol) at −78° C. under nitrogen. Themixture was stirred at rt for 1 h. The reaction mixture was quenchedwith aqueous NH₄Cl solution (50 mL) in ice water bath. The layers wereseparated and the aqueous layer was extracted with EtOAc (150 mL). Thecombined organic phases were washed with brine (30 mL), dried overNa₂SO₄ and concentrated in vacuo to give the crude product, which waspurified by preparative HPLC and chiral HPLC to afford(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(6.6 g, 53%).

Step 3

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(6.6 g, 15.2 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.1 g, 24.3mmol) in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) andPd(dppf)cl₂ (372 mg, 0.46 mmol). After addition, the mixture was allowedto warm to 100° C. for 20 h. After TLC showed the starting material haddisappeared, the solid was filtered off. Water (60 mL) and EtOAc (20 mL)were added. The layers were separated and the aqueous layer wasextracted with EtOAc (3×15 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give aresidue, which was purified by column chromatography to give(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(4.4 g, 60%).

Step 4

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(2.2 g, 4.58 mmol) and 5-bromo-1-methylpyridin-2(1H)-one (1.37 g, 7.33mmol) in dry 1,4-dioxane (4 mL) was added aqueous CsCO₃ solution (10 mL,10 mmol) and Pd(PPh₃)₂Cl₂ (967 mg, 1.38 mmol). After addition, themixture was heated at 110° C. for 30 min in a microwave. After TLCshowed the stating material had disappeared, the solid was filtered off.Water (20 mL) and EtOAc (10 mL) were added. The layers were separatedand the aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give a residue, which was purified by preparative HPLCto give(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(730 mg, 35%). ¹H NMR (CDCl₃): 1.09 (s, 3H), 1.16 (s, 3H), 1.51 (m, 3H),2.05-2.20 (4H), 2.40 (m, 1H), 2.84 (m, 1H), 3.59 (s, 3H), 5.64 (m, 1H),6.62 (m, 1H), 6.96 (m, 2H), 7.14 (m, 2H), 7.28-7.39 (m, 5H), 7.48 (m,1H), 7.50 (m, 1H). The compound was recrystallized by two methods.

Recrystallization Method A

A mixture of(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(ca. 2.94 g) and isopropyl acetate (160 mL) was vigorously stirred atroom temperature or warmed at 50° C. until most of the solid wasdissolved. The resulting mixture was filtered through an HPLC filter andthen the filtrate was slowly stirred at room temperature overnight. Thesolids were filtered, washed with isopropyl acetate and dried at rtunder high vacuum to afford 1.43 g (49%) of a crystalline solid. M.p.95-101° C. This form was determined to be a hydrate which released 3.6%water by weight on heating. Single crystal X-ray crystallography carriedout by procedures similar to those described in Example 48 and 75 showedthat this form was a monohydrate.

Recrystallization Method B

A mixture of(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(ca. 10.03 g) and isopropyl acetate (600 mL) was heated to reflux in a130° C. oil bath until the solid was completely dissolved to form ahomogeneous solution. Heating was stopped and the resulting solution wasslowly stirred while slowly cooling to room temperature in the oil bathovernight. The solids were filtered, washed with isopropyl acetate anddried at rt under high vacuum to afford 7.30 g (73%) of crystallinesolid. M.p. 180˜181° C. This form was determined to be anhydrous.

X-ray Structure Determination of the Monohydrate of Example 37

The monohydrate of Example 37, C₂₈H₃₂N₂O₄.H₂O, crystallizes in themonoclinic space group P2₁ (systematic absences 0k0: k=odd) witha=13.3180(13)Å, b=6.4263(6)Å, c=14.6616(14)Å, β=94.671(3)°,V=1250.7(2)Å³, Z=2 and d_(calc)=1.271 g/cm³. X-ray intensity data werecollected on a Rigaku Mercury CCD area detector employinggraphite-monochromated Mo—K_(α) radiation (λ=0.71073 A) at a temperatureof 143K. Preliminary indexing was performed from a series of twelve 0.5°rotation images with exposures of 30 seconds. A total of 458 rotationimages were collected with a crystal to detector distance of 35 mm, a2θswing angle of −12°, rotation widths of 0.5° and exposures of 45seconds: scan no. 1 was a φ-scan from 135° to 315° at ω=10° and χ=20°;scan no. 2 was an ω-scan from −20° to 5° at χ=−90° and φ=45°; scan no. 3was an ω-scan from −14° to 10° at χ=−90° and φ=0°. Rotation images wereprocessed using CrystalClear (CrystalClear: Rigaku Corporation, 1999.),producing a listing of unaveraged F² and σ(F²) values which were thenpassed to the CrystalStructure (CrystalStructure: Crystal StructureAnalysis Package, Rigaku Corp. Rigaku/MSC (2002)) program package forfurther processing and structure solution on a Dell Pentium IIIcomputer. A total of 7348 reflections were measured over the ranges5.58≦2θ≦50.02°, −14≦η≦15, −6≦κ≦7, −17≦I≦15 yielding 3878 uniquereflections (R_(int)=0.0164). The intensity data were corrected forLorentz and polarization effects and for absorption using REQAB (minimumand maximum transmission 0.844, 1.000).

The structure was solved by direct methods (SIR97 (SIR97: Altomare, A.,M. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A. Guagliardi, A.Moliterni, G. Polidori & R. Spagna (1999). J. Appl. Cryst., 32,115-119)). Refinement was by full-matrix least squares based on F² usingSHELXL-97 (SHELXL-97: Program for the Refinement of Crystal Structures,Sheldrick, G. M. (1997), University of Göttingen, Germany). Allreflections were used during refinement (F²'s that were experimentallynegative were replaced by F²=0). The weighting scheme used wasw=1/[σ²(F_(o) ²)+0.0507P²+0.0056P] where P=(F_(o) ²+2F_(o) ²)/3.Non-hydrogen atoms were refined anisotropically and hydrogen atoms wererefined isotropically. Refinement converged to R₁=0.0327 and wR₂=0.0741for 3641 reflections for which F>4σ(F) and R₁=0.0356, wR₂=0.0770 andGOF=1.071 for all 3878 unique, non-zero reflections and 453 variables:R₁=Σ∥F_(o)|−|F_(c)∥/Σ|F_(o)|wR ₂ ={Σw(F _(o) ² −F _(c) ²)² /Σw(F _(o) ²)²}^(1/2)GOF={Σw(F _(o) ² −F _(o) ²)²/(n−p)}^(1/2)where n=the number of reflections and p=the number of parametersrefined. The maximum Δ/σ in the final cycle of least squares was 0.000and the two most prominent peaks in the final difference Fourier were+0.126 and −0.156 e/Å³.

Table A. lists cell information, data collection parameters, andrefinement data. Final positional and equivalent isotropic thermalparameters are given in Table B. Anisotropic thermal parameters are inTable C.

TABLE A Summary of Structure Determination of the Monohydrate of Example37 Formula: C₂₈H₂N₂O₄•H₂O Formula weight: 478.57 Crystal class:monoclinic Space group: P2₁ (#4) Z 2 Cell constants: a 13.3180(13) Å b6.4263(6) Å c 14.6616(14) Å β 94.671(3)° V 1250.7(2) Å³ μ 0.87 cm⁻¹crystal size, mm 0.34 × 0.12 × 0.07 D_(calc) 1.271 g/cm³ F(000) 512Radiation: Mo—K_(α) (λ = 0.71073 Å) 2θ range 5.58-50.02° hkl collected:−14 ≦ η ≦ 15; −6 ≦ κ ≦ 7; −17 ≦ λ ≦ 15 No. reflections measured: 7348No. unique reflections: 3878 (R_(int) = 0.0164) No. observed reflections3641 (F > 4σ) No. reflections used in refinement 3878 No. parameters 453R indices (F > 4σ) R₁ = 0.0327 wR₂ = 0.0741 R indices (all data) R₁ =0.0356 wR₂ = 0.0770 GOF: 1.071 Final Difference Peaks, e/Å³ +0.126,−0.156

TABLE B Refined Positional Parameters for the Monohydrate of Example 37Atom x y z U_(eq), Å² C1 0.26084(12) 0.6441(3) 0.04394(11) 0.0257(4) C20.18059(11) 0.7202(3) 0.18228(11) 0.0256(4) C3 0.24317(13) 0.3609(3)0.15652(11) 0.0273(4) C4 0.23141(13) 0.4175(3) 0.05530(12) 0.0279(4) C50.20783(13) 0.4862(3) 0.31228(11) 0.0265(4) C6 0.31214(12) 0.4069(3)0.34628(11) 0.0257(4) C7 0.33149(12) 0.2036(3) 0.37391(11) 0.0275(4) C80.42946(12) 0.1350(3) 0.39698(12) 0.0285(4) C9 0.51160(12) 0.2672(3)0.39040(11) 0.0259(4) C10 0.49143(14) 0.4714(3) 0.36273(13) 0.0332(4)C11 0.39419(13) 0.5402(3) 0.34183(13) 0.0337(4) C12 0.61661(12)0.1894(3) 0.40629(10) 0.0261(4) C13 0.69391(12) 0.3119(3) 0.44100(12)0.0288(4) C14 0.81872(12) 0.0435(3) 0.42781(11) 0.0322(4) C150.73791(13) −0.0848(3) 0.39052(13) 0.0347(4) C16 0.64152(13) −0.0148(3)0.38095(13) 0.0316(4) C17 0.11974(13) 0.3459(3) 0.33161(13) 0.0308(4)C18 0.8723(2) 0.3836(4) 0.4866(2) 0.0448(6) C19 0.36756(12) 0.6953(3)0.08492(10) 0.0252(4) C20 0.38835(13) 0.8848(3) 0.12700(12) 0.0322(4)C21 0.48576(14) 0.9382(4) 0.16024(13) 0.0365(5) C22 0.56470(14)0.8013(4) 0.15183(13) 0.0376(5) C23 0.54480(14) 0.6122(4) 0.11008(13)0.0394(5) C24 0.44725(13) 0.5584(3) 0.07634(12) 0.0327(4) C250.25008(13) 0.7270(3) −0.05467(12) 0.0296(4) C26 0.16219(13) 0.6620(3)−0.12314(12) 0.0330(4) C27 0.1729(2) 0.7843(4) −0.21160(14) 0.0426(5)C28 0.0585(2) 0.7030(4) −0.09002(14) 0.0431(5) N1 0.20819(10) 0.5306(2)0.21329(9) 0.0249(3) N2 0.79116(10) 0.2432(3) 0.45199(9) 0.0309(4) O10.18963(8) 0.7664(2) 0.09316(7) 0.0269(3) O2 0.14620(9) 0.8564(2)0.22967(8) 0.0331(3) O3 0.90880(9) −0.0090(3) 0.43797(9) 0.0431(4) O40.17736(10) 0.4451(2) −0.13975(9) 0.0378(3) H3a 0.3181(13) 0.331(3)0.1766(12) 0.028(5) H3b 0.2034(14) 0.229(4) 0.1670(12) 0.033(5) H40.129(2) 0.406(5) −0.189(2) 0.084(9) H4a 0.158(2) 0.400(3) 0.0311(13)0.040(5) H4b 0.272(2) 0.314(4) 0.019(2) 0.048(6) H5 0.1980(13) 0.625(3)0.3374(12) 0.028(5) H7 0.2761(13) 0.104(3) 0.3761(12) 0.029(5) H80.4408(12) −0.012(3) 0.4184(12) 0.027(5) H10 0.551(2) 0.567(4)0.3546(14) 0.044(6) H11 0.383(2) 0.688(4) 0.3194(14) 0.041(5) H130.6829(13) 0.453(4) 0.4616(12) 0.033(5) H15 0.7581(14) −0.231(4)0.3692(13) 0.038(5) H16 0.588(2) −0.102(4) 0.350(2) 0.051(6) H17a0.125(2) 0.202(4) 0.299(2) 0.050(6) H17b 0.1208(13) 0.321(3) 0.3978(14)0.032(5) H17c 0.054(2) 0.412(4) 0.3103(13) 0.039(5) H18a 0.921(2)0.388(5) 0.445(2) 0.079(8) H18b 0.840(2) 0.499(6) 0.510(2) 0.092(10)H18c 0.911(2) 0.315(6) 0.540(2) 0.103(11) H20 0.333(2) 0.980(5) 0.131(2)0.065(7) H21 0.4975(14) 1.079(4) 0.1869(14) 0.043(6) H22 0.636(2)0.834(4) 0.1769(14) 0.049(6) H23 0.600(2) 0.514(4) 0.1029(13) 0.044(6)H24 0.4343(14) 0.427(4) 0.0444(14) 0.038(5) H25a 0.2503(13) 0.882(4)−0.0512(12) 0.030(5) H25b 0.3131(13) 0.680(3) −0.0832(11) 0.023(4) H27a0.124(2) 0.731(4) −0.259(2) 0.042(5) H27b 0.165(2) 0.943(5) −0.197(2)0.066(7) H27c 0.239(2) 0.752(4) −0.2360(14) 0.044(6) H28a 0.0495(14)0.617(4) −0.030(2) 0.048(6) H28b 0.052(2) 0.865(5) −0.076(2) 0.058(7)H28c 0.004(2) 0.655(4) −0.141(2) 0.048(6) O5 −0.04759(10) 0.7816(3)0.28103(11) 0.0424(4) H5a 0.020(2) 0.821(5) 0.272(2) 0.074(8) H5b−0.055(2) 0.834(5) 0.332(2) 0.083(10) U_(eq) = ⅓[U₁₁(aa*)² + U₂₂(bb*)² +U₃₃(cc*)² + 2U₁₂aa*bb*cosγ + 2U₁₃aa*cc*cosβ + 2U₂₃bb*cc*cosα]

TABLE C Refined Thermal Parameters (U's) for the Monohydrate of Example37 Atom U₁₁ U₂₂ U₃₃ U₂₃ U₁₃ U₁₂ C1 0.0236(8) 0.0275(10) 0.0261(9)−0.0028(8) 0.0023(6) 0.0036(7) C2 0.0217(8) 0.0252(10) 0.0300(9)0.0005(8) 0.0018(6) 0.0019(7) C3 0.0336(9) 0.0215(10) 0.0271(9)−0.0028(8) 0.0045(7) 0.0033(8) C4 0.0307(9) 0.0258(10) 0.0267(9)−0.0023(8) 0.0000(7) −0.0016(8) C5 0.0284(9) 0.0259(11) 0.0252(9)−0.0016(8) 0.0019(6) 0.0054(7) C6 0.0273(8) 0.0277(10) 0.0220(8)−0.0030(8) 0.0013(6) 0.0018(7) C7 0.0247(9) 0.0283(10) 0.0302(9)0.0040(8) 0.0049(6) −0.0030(8) C8 0.0276(9) 0.0263(11) 0.0317(9)0.0058(8) 0.0027(7) 0.0010(8) C9 0.0261(8) 0.0281(10) 0.0229(8)−0.0020(8) −0.0011(6) −0.0030(7) C10 0.0306(9) 0.0254(11) 0.0424(10)0.0007(9) −0.0050(7) −0.0061(8) C11 0.0348(10) 0.0211(10) 0.0434(11)−0.0002(9) −0.0071(7) −0.0021(8) C12 0.0262(8) 0.0289(10) 0.0230(8)0.0008(8) 0.0013(6) −0.0020(7) C13 0.0235(9) 0.0348(12) 0.0280(9)−0.0038(8) 0.0018(6) −0.0010(8) C14 0.0297(9) 0.0448(13) 0.0221(8)0.0032(9) 0.0021(6) 0.0042(9) C15 0.0328(10) 0.0318(12) 0.0395(10)0.0026(9) 0.0029(7) 0.0047(9) C16 0.0284(9) 0.0283(11) 0.0376(10)0.0025(9) −0.0001(7) −0.0011(8) C17 0.0262(9) 0.0374(12) 0.0292(10)0.0034(9) 0.0038(7) 0.0032(8) C18 0.0231(9) 0.062(2) 0.0490(12)−0.0180(12) 0.0007(9) −0.0071(10) C19 0.0268(9) 0.0268(10) 0.0225(8)−0.0011(8) 0.0047(6) 0.0008(7) C20 0.0313(9) 0.0317(11) 0.0340(10)−0.0011(9) 0.0044(7) 0.0019(9) C21 0.0379(10) 0.0361(12) 0.0354(10)−0.0036(9) 0.0021(7) −0.0098(9) C22 0.0295(10) 0.0527(14) 0.0303(10)0.0015(10) 0.0011(7) −0.0058(9) C23 0.0269(10) 0.0524(14) 0.0393(11)−0.0022(10) 0.0047(7) 0.0094(10) C24 0.0335(9) 0.0339(12) 0.0310(10)−0.0047(9) 0.0039(7) 0.0050(8) C25 0.0313(9) 0.0306(12) 0.0274(9)0.0036(8) 0.0056(7) 0.0019(8) C26 0.0342(10) 0.0346(12) 0.0295(9)0.0017(9) −0.0007(7) 0.0043(8) C27 0.0501(12) 0.050(2) 0.0281(10)0.0031(10) 0.0021(9) 0.0070(11) C28 0.0337(10) 0.060(2) 0.0351(11)0.0011(11) −0.0005(8) 0.0065(10) N1 0.0282(7) 0.0225(8) 0.0241(7)−0.0002(6) 0.0031(5) 0.0034(6) N2 0.0231(7) 0.0421(11) 0.0273(7)−0.0062(7) 0.0004(5) −0.0018(7) O1 0.0266(6) 0.0277(7) 0.0271(6)0.0028(5) 0.0051(4) 0.0070(5) O2 0.0373(6) 0.0269(7) 0.0364(7)−0.0009(6) 0.0101(5) 0.0095(6) O3 0.0280(7) 0.0620(11) 0.0387(7)0.0003(7) 0.0001(5) 0.0109(6) O4 0.0378(7) 0.0382(8) 0.0358(7)−0.0046(6) −0.0064(5) 0.0040(6) O5 0.0347(8) 0.0494(10) 0.0428(8)−0.0025(8) 0.0019(6) 0.0070(7) The form of the anisotropic displacementparameter is: exp[−2π²(a*²U₁₁h² + b*²U₂₂k² + c*²U₃₃l² + 2b*c*U₂₃kl +2a*c*U₁₃hl + 2a*b*U₁₂hk)].

EXAMPLE 383-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneusing a procedure analogous to that described in Example 29 Step 2followed by treatment with (i) Jones reagent and (ii) NH₃, EDC, HOBt.LC-MS Method 2 t_(R)=1.028 min, m/z=460.2; ¹H NMR (CDCl₃) 1.53 (d, 3H),1.91-2.01 (m, 1H), 2.11-2.42 (m, 5H), 2.46-2.54 (m, 1H), 2.88-2.96 (m,1H), 3.60 (s, 3H), 5.26 (s, 1H), 5.42 (s, 1H), 5.66 (m, 1H), 6.69 (d,1H), 6.95-7.03 (d, 2H), 7.12-7.20 (m, 2H), 7.24-7.41 (m, 5H), 7.52 (m,1H).

EXAMPLE 39N-(3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared from(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneby treatment with (i) MeSO₂C1 and (ii) MeSO₂NH₂, K₂CO₃. LC-MS Method 2t_(R)=1.095 min, m/z=524.1; ¹H NMR (CDCl₃) 1.30-1.41 (m, 1H), 1.52 (d,3H), 1.71 (m, 1H), 1.87-2.07 (m, 3H), 2.09-2.20 (m, 3H), 2.22-2.32 (m,2H), 2.88 (s, 3H), 3.06 (m, 2H), 3.60 (s, 3H), 4.32 (s, 1H), 5.65 (m,1H), 6.67 (d, 1H), 6.94 (m, 2H), 7.11 (d, 2H), 7.25 (m, 1H), 7.27-7.40(m, 4H), 7.53 (dd, 1H).

EXAMPLE 40(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-onefollowing a procedure analogous to that described in Example 18 using5-bromo-1-methylpyridin-2(1H)-one in Step 2. LC-MS Method 2 t_(R)=1.627min, m/z=447.1; ¹H NMR (CDCl₃) 1.06 (m, 3H), 1.87-2.06 (m, 2H),2.11-2.28 (m, 2H), 2.33 (m, 3H), 2.96 (m, 1H), 3.53 (m, 1H), 3.62 (s,3H), 3.78 (m, 1H), 5.48 (m, 1H), 6.69 (m, 1H), 7.03 (m, 2H), 7.14 (m,2H), 7.21-7.38 (m, 4H), 7.41 (s, 1H), 7.56 (m, 1H).

EXAMPLE 41(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-6-(4-fluorophenyl)-3-(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-bromo-2-hydroxypyridine using a procedure analogous to thatdescribed in Example 3 Step 2, followed by a procedure analogous to thatdescribed in Example 29 Step 2. LC-MS Method 1 t_(R)=1.24, m/z=452(M+1);¹H NMR (CDCl₃) 7.76 (d, 1H), 7.52 (d, 1H), 7.42 (dd, 2H), 7.24 (m, 2H),7.08-7.00 (m, 4H), 6.75 (t, 1H), 5.70 (m, 1H), 3.58 (t, 1H), 2.94 (m,1H), 1.54 (d, 3H).

EXAMPLE 42(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(18 mg, 0.039 mmol), 3-bromo-2-hydroxypyridine (14 mg, 2 equiv),Pd(dppf)Cl₂ (3 mg, 10% mol), 2M aq Na₂CO₃ solution (800 μL) and1,4-dioxane (1.5 mL) were mixed. The mixture was evacuated and refilledwith N₂ gas (3×) before being heated overnight at 85° C. After beingcooled to rt, the mixture was filtered and acidified with 5% aq HClsolution before being purified by prep HPLC to afford(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(7.2 mg, 43% yield). LC-MS Method 1 t_(R)=1.57 min, m/z 433 (M+1).

Step 2

A solution of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(15.5 mg, 0.036 mmol) in dry DMF (1 mL) was cooled to 0° C. Sodiumhydride (60% in mineral oil, 3 mg, 2 equiv) was added. After 20 min,iodomethane (4.5 μL, 2 equiv) was added. The mixture was stirred another20 min before being warmed to rt slowly and stirred for 2 h. LC-MS foundthe reaction completed. The mixture was quenched with satd aq NH₄Cl (1mL) and purified by prep HPLC to afford(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(13.3 mg, 83% yield). LC-MS Method 1 t_(R)=1.63 min, m/z 447 (M+1).

Step 3

A solution of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(13.3 mg, 0.030 mmol) in dry THF (1.5 mL) was cooled to 0° C. Disiamylborane (0.5M in THF, 500 μL, excess) was added. After 10 min, themixture was warmed to rt and stirred for 1 h. The mixture was cooled to0° C. again, quenched with water (1 mL) and NaBO₃ (10 mg). The mixturewas concentrated and purified by prep HPLC to afford(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one(4.2 mg, 30% yield). LC-MS Method 1 t_(R)=1.33 min, m/z=487(M+1); ¹H NMR(CD₃Cl) δ 7.47(dd, 1H), 7.38 (m, 3H), 7.24 (m, 2H), 7.07 (t, 2H), 6.96(d, 2H), 6.39 (t, 1H), 5.65 (m, 1H), 4.26 (t, 1H), 3.66 (s, 3H), 2.91(m, 1H), 2.40-2.14 (m, 3H), 1.54 (d, 3H).

EXAMPLE 43(R)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to thosedescribed in Example 30 using ethyl iodide in Step 1, to afford5-bromo-1-ethylpyridin-2(1H)-one which was used in Step 2. LC-MS Method2 t_(R)=1.297 min, m/z=461.1; ¹H NMR (CDCl₃) 1.31 (m, 1H), 1.36 (t, 3H),1.51 (d, 3H), 1.68 (m, 1H), 1.86-2.01 (m, 2H), 2.18 (m, 1H), 2.27 (m,2H), 2.91 (m, 1H), 3.52 (m, 2H), 4.18 (m, 2H), 5.13 (m, 1H), 5.62 (m,1H), 6.91 (m, 3H), 7.08 (m, 2H), 7.18-7.33 (m, 5H), 7.41 (s, 1H), 7.61(d, 1H).

EXAMPLE 44(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 30 Step 2.LC-MS Method 2 t_(R)=1.113 min, m/z=461.1; ¹H NMR (CDCl₃) 0.95 (t, 3H),1.30 (m, 1H), 1.68 (m, 1H), 1.81-1.99 (m, 2H), 2.11-2.32 (m, 3H), 2.88(m, 1H), 3.50 (m, 2H), 3.58 (m, 2H), 5.43 (m, 1H), 6.49 (d, 1H), 6.98(d, 2H), 7.08 (d, 2H), 7.19 (m, 1H), 7.25 (m, 4H), 7.32 (s, 1H), 7.47(m, 1H).

EXAMPLE 45

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2-hydroxypyridine following a procedure analogous to thatdescribed in Example 30 Step 2. LC-MS Method 2 t_(R)=1.019 min,m/z=865.4; ¹H NMR (CDCl₃) 1.29-1.40 (m, 1H), 1.49 (d, 3H), 1.60-1.72 (m,1H), 1.83-2.01 (m, 3H), 2.18 (m, 1H), 2.21-2.37 (m, 2H), 2.88 (m, 1H),3.51 (m, 2H), 5.63 (m, 1H), 6.41 (d, 1H), 6.68 (s, 1H), 6.90 (d, 2H),7.21-7.33 (m, 7H), 7.39 (d, 1H).

EXAMPLE 46(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 6-bromo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 30 Step 2. LC-MS Method 2 t_(R)=1.088 min,m/z=447; ¹H NMR (CDCl₃) 1.38 (m, 1H), 1.56 (d, 3H), 1.70 (m, 1H),1.95-2.08 (m, 2H), 2.23 (m, 1H), 2.37 (s, 2H), 3.05 (m, 1H), 3.33 (s,3H), 3.58 (m, 2H), 5.73 (m, 1H), 6.29 (d, 1H), 6.89 (d, 1H), 7.01-7.09(m, 4H), 7.21-7.39 (m, 5H), 7.53 (t, 1H).

6-Bromo-1-methylpyridin-2(1H)-one was prepared from6-bromopyridin-2(1H)-one following a procedure analogous to thatdescribed in Example 59 Step 1.

EXAMPLE 47(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a suspension of NaH (80 mg, 2 mmol) in THF (10 mL) was added4-bromopyridin-2-ol (80 mg, 0.46 mmol) at 0° C. The resulting mixturewas stirred for 1 h. Then CH₃I (355 mg, 2.5 mmol) was added to the abovemixture, and the mixture was stirred overnight. The reaction wasquenched with aqueous NH₄Cl solution. The organic phase was concentratedto give the crude product, which was purified by column to give4-bromo-1-methylpyridin-2(1H)-one (42.3 mg, 50%).

Step 2

A mixture of(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(50 mg, 0.11 mmol) and 4-bromo-1-methylpyridin-2(1H)-one (30 mg, 0.16mmol), Pd(Ph₃P)₂Cl₂ (10 mg), and aq. Cs₂CO₃ solution (4 mL, 2 M) in1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. When thereaction was over, the mixture was washed with water and extracted withEtOAc. The organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedby preparative TLC to give(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(25 mg, 51%). ¹H NMR (CDCl₃): δ=1.35 (m, 1H), 1.47 (d, 3H), 1.63 (m,2H), 1.94 (m, 2H), 2.18 (m, 1H), 2.39 (m, 2H), 2.86 (m, 1H), 3.51 (m,5H), 5.63 (m, 1H), 6.31 (m, 1H), 6.70 (m, 1H), 6.91 (m, 2H), 7.20-7.32(m, 8H).

EXAMPLE 48(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Method 1

Step 1

A solution of 4-bromopyridin-2-amine (600 mg, 3.5 mmol) in a mixture of2 M H₂SO₄ (20 mL) and 2 M Na₂NO₂ (10 mL) was stirred at 0-5° C. for 2 h.The reaction mixture was extracted with CH₂Cl₂, and the organic layerwas washed with a saturated NaCl solution, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by preparative TLC to give4-bromopyridin-2-ol (303 mg, 50%).

Step 2

To a suspension of NaH (300 mg, 7.5 mmol) in THF (10 mL) was added4-bromopyridin-2-ol (303 mg, 1.73 mmol) at 0° C. After the resultingmixture was stirred for 1 h, CH₃I (491 mg, 3.46 mmol) was added, and themixture was stirred overnight. The reaction was quenched with aqueousNH₄Cl solution. The organic phase was concentrated to give the crudeproduct, which was purified by column to give4-bromo-1-methylpyridin-2(1H)-one (161 mg, 50%).

Step 3

A mixture of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(200 mg, 0.42 mmol), 4-bromo-1-methylpyridin-2(1H)-one (118 mg, 0.63mmol), Pd(Ph₃P)₂Cl₂ (20 mg), and 2 M aq Cs₂CO₃ solution (5 mL, 10 mmol)in 1,4-dioxane (20 mL) was stirred and heated to reflux for 2 h. Whenthe reaction was finished, the mixture was washed with water andextracted with EtOAc. The organic phase was washed with brine, driedover Na₂SO₄, filtered, and concentrated to give the crude product, whichwas purified by preparative TLC to give(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(83 mg, 43%). LC-MS Method 2 t_(R)=1.16 min, m/z=921.5; ¹H NMR (CDCl₃)1.11 (s, 3H), 1.18 (s, 3H), 1.22 (t, 1H), 1.52 (m, 3H), 2.21 (s, 2H),2.22-2.34 (m, 2H), 2.34-2.46 (m, 1H), 2.85 (m, 1H), 3.57 (s, 3H), 5.59(m, 1H), 6.33 (d, 1H), 6.68 (s, 1H), 7.01 (d, 2H), 7.29-7.41 (m, 8H); ¹HNMR (CD₃OD) 0.98 (s, 3H), 1.29 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.22(m, 1H), 2.50 (m, 2H), 3.08 (m, 1H), 3.59 (s, 3H), 5.59 (m, 1H), 6.61(d, 1H), 6.66 (s, 1H), 7.08 (m, 2H), 7.30-7.40 (5H), 7.42 (d, 2H), 7.70(d, 1H).

Method 2

Step 1

To a solution of 4-iodopyridin-2(1H)-one (3 g, 0.013 mol) and K₂CO₃(3.55 g, 0.026 mol) in DMF (30 mL) was added iodomethane (4.7 g, 0.033mmol). The mixture was stirred at room temperature overnight. Water andEtOAc were added. The organic phase was dried over Na₂SO₄ andconcentrated to give 4-iodo-1-methylpyridin-2(1H)-one (1.6 g, 53%).

Step 2

A mixture of 4-iodo-1-methylpyridin-2(1H)-one (0.909 g, 3.76 mmol),(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(1.5 g, 3.13 mmol), 2 M aq Cs₂CO₃ (3 mL, 6 mmol), and PdCl₂(PPh₃)₂(0.201 g, 0.282 mmol) in 1,4-dioxane (15 mL) was refluxed under N₂ for 2hours. The reaction mixture was filtered, and the filtrate was extractedwith EtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated to obtain the crude compound, which was purifiedby preparative HPLC and chiral HPLC to obtain(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(399 mg, 28%). LC-MS and ¹H NMR (CD₃OD) were the same as those ofproduct made by Method 1. The compound was recrystallized using belowmethods.

The compound was obtained as a crystalline monohydrate by dropwiseaddition of 60 mL of water to a solution of 7.6 g of compound in 15 mLof methanol. After stirring for 1 h, the solid is filtered by suction,washed with water and diethylether and dried in an exsiccator over conc.sulphuric acid/potassium hydroxide. The compound was also recrystallizedfrom water/ethanol (80:20) to also yield the monohydrate. Melting point:118-122° C.

The compound was recrystallized from isopropyl acetate following aprocedure analogous to that described for Example 37 inRecrystallization Method B to give a crystalline solid with mp 106-116°C. The compound was also recrystallized by this method from EtOAc (mp90-93° C.), from EtOAc/iPr₂O (mp 102-122° C.) from isobutyl acetate (mp108-126° C.), from EtOH/TBME (mp 108-126° C.) and from 2-butanone.

This crystalline form may be characterized by means of itscharacteristic X-ray powder diffraction (XRPD) patterns.

The crystalline form is characterised by an X-ray powder diffractionpattern that comprises peaks at 8.71, 12.93 and 19.16 degrees 2Θ (±0.05degrees 2Θ, wherein said X-ray powder diffraction pattern is made usingCuK_(α1) radiation.

In particular said X-ray powder diffraction pattern comprises peaks at8.71, 12.93, 19.16, 19.45 and 21.06 degrees 2Θ (±0.05 degrees 2Θ,wherein said X-ray powder diffraction pattern is made using CuK_(α1)radiation.

More specifically, the crystalline form is characterised by followinglattice parameters: orthorhombic symmetry, space group P2₁2₁2₁ with thecell parameters, a=9.28(1)Å, b=11.06(2)Å, c=25.52(2)Å, and cellvolume=2616(5)Å³ obtained by indexing of the X-ray powder diagrammeasured at room temperature using CuK_(α1) radiation, which comprisespeaks at degrees 2Θ (±0.05 degrees 2Θ as contained in Table 1.

TABLE 1 Indexed XRPD peaks up to 30° 2Θ including intensities(normalised) of the monohydrate of Example 48 2Θ d_(hkl) IntensityIndexing 2Θ_(obs) − 2Θ_(calc) [°] [Å] I/I_(o) [%] h k l [°] 6.90 12.8013 0 0 2 −0.024 8.71 10.14 100 0 1 1 0.003 10.13 8.73 12 1 0 1 −0.01210.58 8.36 32 0 1 2 −0.004 11.78 7.51 1 1 0 2 −0.007 12.45 7.10 42 1 1 00.004 12.93 6.84 91 1 1 1 0.007 13.86 6.39 29 0 0 4 −0.016 14.26 6.21 521 1 2 0.002 16.05 5.52 39 0 2 0 0.035 16.26 5.45 41 1 1 3 0.015 16.425.39 49 0 2 1 0.030 17.48 5.07 2 0 2 2 0.014 18.68 4.75 39 1 2 0 0.01319.16 4.63 76 2 0 0 0.041 19.45 4.56 70 2 0 1 0.010 19.96 4.44 44 1 2 20.028 20.37 4.36 52 2 0 2 0.006 20.77 4.27 18 2 1 0 0.016 21.06 4.22 572 1 1 0.011 21.43 4.14 38 1 2 3 0.012 21.87 4.06 54 2 1 2 −0.038 22.383.97 18 0 1 6 <0.001 23.36 3.81 4 1 2 4 0.023 23.73 3.75 16 2 0 4 0.02724.39 3.65 17 1 1 6 0.013 25.18 3.53 13 0 3 2 0.046 25.69 3.46 13 0 1 7−0.023 26.31 3.38 8 0 3 3 −0.026 26.41 3.37 7 0 2 6 −0.009 27.21 3.28 322 2 3 0.027 27.48 3.24 5 1 1 7 0.003 28.14 3.17 4 1 2 6 −0.011 28.773.10 7 2 2 4 0.030 29.10 3.07 2 3 0 1 0.032 29.34 3.04 5 0 2 7 0.01729.71 3.00 19 3 0 2 0.004 29.95 2.98 13 3 1 0 −0.037

The X-ray powder diffraction patterns are recorded, within the scope ofthe present invention, using a STOE-STADI P-diffractometer intransmission mode fitted with a position-sensitive detector (PSD) and aCu-anode as X-ray source and a Germanium monochromator (CuK_(α1)radiation, λ=1,54056 Å,40 kV, 40 mA). In the Table 1 above the values“2Θ[°]” denote the angle of diffraction in degrees and the values“d_(hkl), [Å]” denote the specified distances in A between the latticeplanes. The intensity shown in the FIG. 1 is given in units of cps(counts per second).

The crystalline form is characterised by an X-ray powder diffractionpattern, made using CuK_(α1) radiation, which comprises peaks at degrees2Θ (±0.05 degrees 2Θ as shown in FIG. 1.

In order to allow for experimental error, the above described 2Θ valuesshould be considered accurate to ±0.05 degrees 2Θ. That is to say, whenassessing whether a given sample of crystals of the compound A is thecrystalline form I in accordance with the invention, a 2Θ value which isexperimentally observed for the sample should be considered identicalwith a characteristic value described above if it falls within ±0.05degrees 2Θ of the characteristic value.

X-ray Structure Determination of the Monohydrate of Example 48

The monohydrate of Example 48, C₂₉H₃₄NO₅, crystallizes in theorthorhombic space group P2₁2₁2₁ (systematic absences h00: h=odd, 0k0:k=odd, and 00l: l=odd) with a=9.2099(11)Å, b=11.0051(11)Å, c=25.456(3)Å,V=2580.1(5)Å³, Z=4 and d_(calc)=1.227 g/cm³. X-ray intensity data werecollected on a Rigaku Mercury CCD area detector employinggraphite-monochromated Mo—K_(α) radiation (λ=0.71073 Å) at a temperatureof 170K. Preliminary indexing was performed from a series of twelve 0.5°rotation images with exposures of 30 seconds. A total of 350 rotationimages were collected with a crystal to detector distance of 35 mm, a 2θswing angle of −12°, rotation widths of 0.5° and exposures of 20seconds: scan no. 1 was a φ-scan from 150° to 300° at ω=10° and χ=20°;scan no. 2 was an ω-scan from −20° to 5° at χ=−90° and φ=135°. Rotationimages were processed using CrystalClear (CrystalClear (CrystalClear:Rigaku Corporation, 1999), producing a listing of unaveraged F² andσ(F²) values which were then passed to the CrystalStructure(CrystalStructure: Crystal Structure Analysis Package, Rigaku Corp.Rigaku/MSC (2002)) program package for further processing and structuresolution on a Dell Pentium III computer. A total of 11320 reflectionswere measured over the ranges 5.46≦2θ≦50.04°, −8≦h≦10, −13≦k≦10,−30≦I≦24 yielding 4448 unique reflections (R_(int)=0.0192). Theintensity data were corrected for Lorentz and polarization effects andfor absorption using REQAB (minimum and maximum transmission 0.822,1.000).

The structure was solved by direct methods (SIR97) (SIR97: Altomare, A.,M. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A. Guagliardi, A.Moliterni, G. Polidori & R. Spagna (1999). J. Appl. Cryst., 32,115-119). Refinement was by full-matrix least squares based on F² usingSHELXL-97(SHELXL-97: Program for the Refinement of Crystal Structures,Sheldrick, G. M. (1997), University of Göttingen, Germany). Allreflections were used during refinement. The weighting scheme used wasw=1/[σ²(F_(o) ²)+0.0501P²+0.2402P] where P=(F_(o) ²+2 F_(c) ²)/3.Non-hydrogen atoms were refined anisotropically and hydrogen atoms wererefined using a “riding” model. Refinement converged to R₁=0.0357 andwR₂=0.0873 for 4119 reflections for which F>4σ (F) and R₁=0.0399,wR₂=0.0917 and GOF=1.080 for all 4448 unique, non-zero reflections and323 variables:R ₁ =Σ∥F _(o) |−|F _(c) ∥/Σ|F _(o)|wR ₂ ={Σw(F _(o) ² −F _(c) ²)²/Σ(F _(o) ²)²}^(1/2)GOF={Σw(F _(o) ² −F _(c) ²)²/(n−p)}^(1/2)where n=the number of reflections and p=the number of parametersrefined.

The maximum Δ/σ in the final cycle of least squares was 0.000 and thetwo most prominent peaks in the final difference Fourier were +0.142 and−0.137 e/Å³.

Table 1A. lists cell information, data collection parameters, andrefinement data. Final positional and equivalent isotropic thermalparameters are given in Table 1B. Anisotropic thermal parameters are inTable 1C.

TABLE 1A Summary of Structure Determination of the Monohydate of Example48 Formula: C₂₉H₃₄NO₅ Formula weight: 476.57 Crystal class: orthorhombicSpace group: P2₁2₁2₁ (#19) Z 4 Cell constants: a 9.2099(11) Å b11.0051(11) Å c 25.456(3) Å V 2580.1(5) Å³ μ 0.83 cm⁻¹ crystal size, mm0.32 × 0.22 × 0.20 D_(calc) 1.227 g/cm³ F(000) 1020 Radiation:Mo—K_(α)(λ = 0.71073 Å) 2θ range 5.46-50.04° hkl collected: −8 ≦ h ≦ 10;−13 ≦ k ≦ 10; −30 ≦ l ≦ 24 No. reflections measured: 11320 No. uniquereflections: 4448 (R_(int) = 0.0192) No. observed reflections 4119 (F >4σ) No. reflections used in refinement 4448 No. parameters 323 R indices(F > 4σ) R₁ = 0.0357 wR₂ = 0.0873 R indices (all data) R₁ = 0.0399 wR₂ =0.0917 GOF: 1.080 Final Difference Peaks, e/Å³ +0.142, −0.137

TABLE 1B Refined Positional Parameters for The Monohydrate of Example 48Atom X Y Z U_(eq), Å² C1 0.5301(2) 0.5918(2) 0.33496(7) 0.0316(4) C20.7452(2) 0.7096(2) 0.35792(6) 0.0323(4) C3 0.5174(2) 0.7392(2)0.40836(7) 0.0367(4) H3a 0.4759 0.8163 0.4191 0.049 H3b 0.5014 0.68100.4364 0.049 C4 0.4434(2) 0.6956(2) 0.35879(7) 0.0351(4) H4a 0.43650.7618 0.3338 0.047 H4b 0.3459 0.6681 0.3669 0.047 C5 0.7598(2)0.8066(2) 0.44350(7) 0.0374(4) H5 0.8622 0.8025 0.4332 0.050 C60.7410(2) 0.7237(2) 0.49076(7) 0.0352(4) C7 0.6725(2) 0.7583(2)0.53701(7) 0.0364(4) H7 0.6425 0.8384 0.5412 0.048 C8 0.6482(2)0.6754(2) 0.57705(7) 0.0371(4) H8 0.6030 0.7011 0.6078 0.049 C90.6902(2) 0.5544(2) 0.57218(7) 0.0352(4) C10 0.7651(2) 0.5206(2)0.52640(7) 0.0391(4) H10 0.7984 0.4413 0.5227 0.052 C11 0.7899(2)0.6036(2) 0.48700(7) 0.0389(4) H11 0.8403 0.5794 0.4571 0.052 C120.6520(2) 0.4631(2) 0.61269(7) 0.0377(4) C13 0.6253(2) 0.3449(2)0.59925(8) 0.0424(4) H13 0.6319 0.3232 0.5640 0.056 C14 0.5880(2)0.2537(2) 0.63613(7) 0.0405(4) C15 0.6009(2) 0.4096(2) 0.70166(8)0.0471(5) H15 0.5916 0.4315 0.7368 0.063 C16 0.6388(2) 0.4956(2)0.66659(7) 0.0441(5) H16 0.6562 0.5749 0.6774 0.059 C17 0.7240(3)0.9403(2) 0.45250(8) 0.0525(5) H17a 0.7381 0.9846 0.4204 0.079 H17b0.7866 0.9725 0.4792 0.079 H17c 0.6247 0.9478 0.4635 0.079 C18 0.5347(3)0.2018(2) 0.72771(7) 0.0497(5) H18a 0.5388 0.2382 0.7619 0.075 H18b0.6008 0.1344 0.7262 0.075 H18c 0.4378 0.1736 0.7210 0.075 C19 0.5527(2)0.4858(2) 0.37321(7) 0.0337(4) C20 0.6853(2) 0.4263(2) 0.37745(7)0.0396(4) H20 0.7643 0.4537 0.3580 0.053 C21 0.7016(2) 0.3261(2)0.41037(8) 0.0493(5) H21 0.7910 0.2872 0.4129 0.066 C22 0.5851(3)0.2846(2) 0.43922(8) 0.0528(5) H22 0.5958 0.2181 0.4614 0.070 C230.4521(3) 0.3421(2) 0.43508(8) 0.0532(5) H23 0.3732 0.3139 0.4544 0.071C24 0.4359(2) 0.4415(2) 0.40230(8) 0.0442(5) H24 0.3459 0.4792 0.39960.059 C25 0.4685(2) 0.5389(2) 0.28381(7) 0.0338(4) H25a 0.3889 0.48580.2936 0.045 H25b 0.5434 0.4875 0.2689 0.045 C26 0.4127(2) 0.6206(2)0.23918(7) 0.0375(4) C27 0.3582(3) 0.5387(2) 0.19492(8) 0.0537(6) H27a0.2852 0.4847 0.2083 0.081 H27b 0.4377 0.4921 0.1812 0.081 H27c 0.31750.5877 0.1674 0.081 C28 0.5254(2) 0.7077(2) 0.21787(8) 0.0465(5) H28a0.4840 0.7543 0.1897 0.070 H28b 0.6072 0.6626 0.2050 0.070 H28c 0.55650.7615 0.2454 0.070 N1 0.6739(2) 0.75380(12) 0.39953(6) 0.0332(3) N20.5755(2) 0.29203(14) 0.68795(6) 0.0408(4) O1 0.67306(12) 0.64280(10)0.32157(4) 0.0337(3) O2 0.87528(13) 0.72746(12) 0.34976(5) 0.0419(3) O30.2937(2) 0.69479(12) 0.25654(5) 0.0482(3) H3 0.2391 0.6541 0.2750 0.072O4 0.5655(2) 0.14473(13) 0.62470(6) 0.0549(4) O5 1.1026(2) 0.57570(12)0.32703(7) 0.0597(4) H5a 1.0135 0.6229 0.3334 0.037 H5b 1.0862 0.50120.3412 0.037 U_(eq) = ⅓[U₁₁(aa*)² + U₂₂(bb*)² + U₃₃(cc*)² +2U₁₂aa*bb*cosγ + 2U₁₃aa*cc*cosβ + 2U₂₃bb*cc*cosα]

TABLE 1C Refined Thermal Parameters (U's) for the Monohydrate of Example48 Atom U₁₁ U₂₂ U₃₃ U₂₃ U₁₃ U₁₂ C1 0.0268(8) 0.0321(9) 0.0359(9)−0.0022(7) 0.0012(7) 0.0000(7) C2 0.0299(9) 0.0324(9) 0.0345(9)0.0001(7) −0.0011(8) 0.0013(7) C3 0.0273(9) 0.0436(10) 0.0392(10)−0.0095(8) 0.0011(7) 0.0002(7) C4 0.0290(8) 0.0384(10) 0.0379(10)−0.0052(8) −0.0019(7) 0.0035(7) C5 0.0351(9) 0.0422(10) 0.0350(9)−0.0019(8) −0.0048(8) −0.0074(8) C6 0.0288(8) 0.0424(11) 0.0345(9)−0.0039(8) −0.0049(8) −0.0037(8) C7 0.0309(9) 0.0381(10) 0.0402(10)−0.0053(8) −0.0036(8) 0.0023(8) C8 0.0300(9) 0.0455(11) 0.0359(10)−0.0068(8) −0.0006(8) 0.0018(8) C9 0.0322(9) 0.0385(10) 0.0350(9)−0.0051(8) −0.0021(8) −0.0001(8) C10 0.0398(10) 0.0366(10) 0.0409(10)−0.0048(8) −0.0008(8) 0.0049(8) C11 0.0364(10) 0.0451(11) 0.0354(10)−0.0072(8) 0.0014(8) 0.0009(8) C12 0.0329(9) 0.0425(10) 0.0376(10)−0.0020(8) −0.0018(8) 0.0021(8) C13 0.0471(11) 0.0457(11) 0.0344(10)−0.0038(9) −0.0001(9) −0.0022(9) C14 0.0390(10) 0.0440(11) 0.0385(10)−0.0010(9) −0.0012(8) −0.0004(8) C15 0.0561(13) 0.0486(12) 0.0365(10)−0.0047(9) 0.0020(10) 0.0049(10) C16 0.0517(12) 0.0426(11) 0.0379(10)−0.0054(9) 0.0006(9) 0.0022(9) C17 0.0699(14) 0.0414(11) 0.0462(11)−0.0014(9) −0.0082(11) −0.0139(10) C18 0.0620(14) 0.0480(11) 0.0392(11)0.0064(9) 0.0059(10) 0.0066(10) C19 0.0361(9) 0.0336(9) 0.0315(9)−0.0042(7) −0.0042(8) 0.0008(8) C20 0.0400(10) 0.0351(10) 0.0436(10)−0.0033(8) −0.0024(9) 0.0037(8) C21 0.0540(12) 0.0405(11) 0.0535(12)−0.0036(9) −0.0105(10) 0.0083(9) C22 0.075(2) 0.0377(10) 0.0460(11)0.0038(9) −0.0098(11) 0.0008(11) C23 0.0603(13) 0.0492(11) 0.0500(12)0.0069(10) 0.0089(11) −0.0064(11) C24 0.0426(11) 0.0445(11) 0.0455(11)0.0020(9) 0.0023(9) 0.0016(9) C25 0.0356(10) 0.0302(9) 0.0356(10)−0.0023(8) −0.0005(8) 0.0009(7) C26 0.0422(11) 0.0372(10) 0.0331(10)−0.0020(8) −0.0034(8) 0.0031(8) C27 0.070(2) 0.0486(12) 0.0426(11)−0.0030(10) −0.0159(11) −0.0034(10) C28 0.0509(12) 0.0432(11) 0.0454(11)0.0082(9) −0.0030(9) −0.0005(9) N1 0.0273(7) 0.0387(8) 0.0338(8)−0.0034(7) −0.0014(6) −0.0014(6) N2 0.0431(9) 0.0445(9) 0.0349(8)−0.0006(7) 0.0012(7) 0.0038(7) O1 0.0291(6) 0.0383(7) 0.0338(6)−0.0045(5) 0.0011(5) −0.0005(5) O2 0.0293(7) 0.0523(8) 0.0442(7)−0.0029(6) 0.0047(5) −0.0046(6) O3 0.0423(8) 0.0510(8) 0.0513(8)0.0028(7) −0.0043(6) 0.0114(6) O4 0.0706(10) 0.0446(8) 0.0494(8)−0.0035(7) 0.0011(8) −0.0096(7) O5 0.0511(9) 0.0428(8) 0.0850(11)0.0016(8) 0.0162(8) 0.0038(7) The form of the anisotropic displacementparameter is: exp[−2π²(a*²U₁₁h² + b*²U₂₂k² + c*²U₃₃l² + 2b*c*U₂₃kl +2a*c*U₁₃hl + 2a*b*U₁₂hk)].

To investigate the stability of the monohydrate of Example 48, a slurryexperiment was performed. In this study, a suspension of the monohydrateof Example 48 was suspended in water for up to seven days. After thetreatment, the mixtures were filtered and an x-ray powder diffraction ofthe filtration residue was measured. No polymorphic change was observedfor the monohydrate of Example 48. In contrast, the anhydrous form ofExample 48 did not remain in the anhydrous state during the measurementby XRPD (30 minutes).

Method 3

Step 1

A mixture of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(100 mg, 0.23 mmol),2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68mg, 1.25 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (19 mg, 10% mol), 2M aq Na₂CO₃ (1mL), 1,4-dioxane (3 mL) was degassed, refilled with N₂ gas for 3 timesbefore being put into microwave oven for 2 h at 130° C. LC-MS found thereaction was completed. The mixture was diluted with EtOAc (50 mL),washed with water (10 mL) and brine (8 mL), and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by chromatographyon a 12-g silica gel column, eluted with a 0 to 10% MeOH in CH₂Cl₂gradient to afford(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(112 mg, quant yield). LC-MS Method 1 t_(R)=1.66 min, m/z=461(M+1).

Step 2

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv), andIodomethane (40 μL, 10 equiv) were mixed with acetonitrile (2.5 mL) andheated at reflux for 4 h. After being cooled to rt, the mixture wasacidified with 5% aq HCl and purified by prep HPLC to afford(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(14.4 mg. 52%). LC-MS and ¹H NMR (CD₃OD) were the same as those ofproduct made by Method 1.

EXAMPLE 492,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

Method 1

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 6 Step 1. LC-MS Method 2 t_(R)=1.231 min,m/z=470.1; ¹H NMR (CDCl₃) 1.28 (s, 3H), 1.40 (s, 3H), 1.47 (d, 3H), 2.09(s, 2H), 2.21 (m, 1H), 2.41 (m, 2H), 2.83 (m, 1H), 3.52 (s, 3H), 5.56(m, 1H), 6.58 (d, 1H), 6.82 (d, 2H), 7.02 (d, 2H), 7.30 (m, 6H), 7.43(m, 1H).

Method 2

A solution of2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile(202 mg, 0.444 mmol) and MeI (110 μL, 4 equiv) in dry THF (5 mL) wascooled to 0° C. NaH (60% in mineral oil, 36 mg, 2 equiv) was added.After 10 min, the mixture was warmed to rt slowly and stirred for 3 h.LC-MS showed about 50% conversion. The mixture was heated for 1 h at 60°C. LC-MS found the reaction completed. After cooling to rt, the mixturewas cooled to 0° C. and quenched with satd aq NH₄Cl (3 mL). The mixturewas then diluted with CH₂Cl₂ (20 mL), washed with 1% aq HCl (5 mL) andbrine (4 mL), and dried over Na₂SO₄. After filtration and concentration,the residue was purified by prep HPLC to afford2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile(177.4 mg, 85% yield) product as a light brown oil.

Method 3

2,2-Dimethyl-3-(3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-2-oxo-(S)-6-phenyl-[1,3]oxazinan-6-yl)-propionitrilewas prepared from(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-onefollowing procedures analogous to those described Example 71 Method 2 toprepare3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile.(S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one,is obtained from coupling(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-onewith 5-iodo-1-methyl-1H-pyridin-2-one by the action of Pd(PPh₃)₄ and 2 Maqueous Na₂CO₃ solution in a mixture of methanol and dioxane (1:3) at80° C. The compound that had been obtained as a foam was dissolved in asmall amount of ethyl acetate and stirred overnight at rt. The solid wasfiltered by suction, washed with a small amount of diethylether anddried. Melting point: 143-145° C.

EXAMPLE 502,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

Method 1

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 4-bromo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 6 Step 1. LC-MS Method 2 t_(R)=1.103,m/z=470.4; ¹H NMR (CDCl₃) 1.26 (s, 3H), 1.41 (s, 3H), 1.49 (d, 3H), 2.09(s, 2H), 2.24 (m, 1H), 2.53 (m, 2H), 2.88 (m, 1H), 3.56 (s, 3H), 5.59(m, 1H), 6.38 (d, 1H), 6.78 (s, 1H), 6.84 (d, 2H), 7.19 (m, 2H), 7.31(m, 6H).

Method 2

(S)-2,2-Dimethyl-3-(3-{1-[(S)-4-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-2-oxo-6-phenyl-[1,3]oxazinan-6-yl)-propionitrilewas prepared from(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 71 Method 2to prepare3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile.The starting compound,(S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one,is obtained from coupling(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-onewith trifluoro-methanesulfonic acid1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl ester employing the standardconditions, Pd(dppf)Cl₂*CH₂Cl₂, 2 M aqueous Na₂CO₃ solution, DMF, 90°C., 2 h. The compound that had been obtained as a resin was dissolved ina small amount of EtOAc and stirred overnight at rt. The solid wasfiltered by suction, washed with a small amount of diethylether anddried. Melting point: 195-198° C.

EXAMPLE 512,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 4-bromo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 6 Step 1, followed by treatment with H₂O₂,K₂CO₃. LC-MS Method 2 t_(R)=1.133 min, m/z=488.1; ¹H NMR (CDCl₃) 1.12(s, 3H), 1.19 (s, 3H), 1.49 (d, 3H), 2.09-2.28 (m, 3H), 2.32-2.58 (m,2H), 2.89 (m, 1H), 3.59 (s, 3H), 5.61 (m, 1H), 6.54 (m, 1H), 6.88 (m,1H), 6.97-7.10 (m, 2H), 7.28 (m, 6H), 7.42 (m, 1H), 7.53 (m, 1H).

EXAMPLE 52(S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-onefollowing a procedure analogous to that described in Example 32 Method 2using 5-bromo-1-ethylpyridin-2(1H)-one in Step 4. LC-MS Method 2t_(R)=1.732 min, m/z=475.1; ¹H NMR (CDCl₃) 0.95 (s, 3H), 1.01 (t, 3H),1.26 (s, 3H), 1.38 (t, 3H), 2.06 (m, 2H), 2.18-2.31 (m, 3H), 2.36 (m,1H), 2.55 (m, 1H), 3.04 (m, 1H), 4.11 (m, 2H), 5.37 (m, 1H), 6.66 (d,1H), 7.11 (m, 2H), 7.20-7.33 (m, 7H), 7.76 (d, 1H), 7.88 (s, 1H).

EXAMPLE 53(S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-1-ethylpyridin-2(1H)-one following a procedure analogous tothat described in Example 6 Step 1. LC-MS Method 2 t_(R)=1.224 min,m/z=475.1; ¹H NMR (CDCl₃) 1.11 (s, 3H), 1.19 (s, 3H), 1.39 (t, 3H), 1.56(d, 3H), 2.20 (s, 2H), 2.26 (m, 1H), 2.36-2.57 (m, 2H), 2.87 (m, 1H),4.03 (m, 2H), 5.69 (m, 1H), 6.62 (d, 1H), 7.00 (d, 2H), 7.17 (d, 2H),7.28-7.51 (m, 6H), 7.50 (d, 1H). Recrystallization from isopropylacetate following a procedure analogous to that described for Example 37in Recrystallization Method B afforded a crystalline solid with mp167-168° C.

EXAMPLE 54(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-onefollowing a procedure analogous to that described in Example 32 Method 2using 5-bromo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 2t_(R)=1.746 min, m/z=475.2; ¹H NMR (CD₃OD) 1.04 (t, 3H), 1.11 (s, 3H),1.24 (s, 3H), 1.95-2.04 (m, 2H), 2.13-2.26 (m, 4H), 2.44 (m, 1H), 2.91(m, 1H), 3.61 (s, 3H), 5.36 (m, 1H), 6.67 (d, 1H), 7.10-7.33 (m, 8H),7.42 (s, 1H), 7.55 (d, 1H).

EXAMPLE 55(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 4-bromo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 59 Step 2. LC-MS Method 2 t_(R)=1.203 min,m/z=971.4; ¹H NMR (CDCl₃) 0.97 (t, 3H), 1.12 (s, 3H), 1.19 (s, 3H),1.79-2.02 (m, 2H), 2.11-2.24 (m, 4H), 2.29-2.42 (m, 1H), 2.81 (m, 1H),3.50 (s, 3H), 5.40 (m, 1H), 6.28 (d, 1H), 6.64 (s, 1H), 7.02 (d, 2H),7.18 (m, 3H), 7.20 (m, 2H), 7.28 (m, 3H).

EXAMPLE 56(R)-6-ethyl-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 32 Method 2Steps 3 and 4. LC-MS Method 1 t_(R)=1.6 min, m/z=431 (M+1).

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-onewas prepared from 1-chloro-3-phenylpentan-3-ol and(S)-1-(4-bromophenyl)propan-1-amine following a procedure analogous tothat described in Example 71 Step 2.

1-chloro-3-phenylpentan-3-ol was prepared from3-chloro-1-phenylpropan-1-one and ethylmagnesium bromide following aprocedure analogous to that described in Preparation 1 Method 1 Step 2.

EXAMPLE 57(R)-6-ethyl-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 32 Method 2Steps 3 and 4 using 5-bromo-1-ethylpyridin-2(1H)-one in Step 4. LC-MSMethod 1 t_(R)=1.68 min, m/z=445 (M+1).

EXAMPLE 58(R)-6-ethyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 32 Method 2Steps 3 and 4 using 4-iodo-1-methylpyridin-2(1H)-one in Step 4. LC-MSMethod 1 t_(R)=1.58 min, m/z=431 (M+1); ¹H NMR (CDCl₃) 7.33 (1H, d,J=7.03 Hz), 7.29-7.21 (7H, m), 7.01 (2H, d, J=8.20 Hz), 6.75 (1H, d,J=2.05), 6.39 (1H, dd, J=2.05, 7.03), 5.48 (1H, ap dd, J=6.44, 9.66),3.58 (3H, s), 2.95-2.87 (1H, m), 2.37-2.14 (3H, m), 2.06-1.81 (m, 4H),1.00 (3H, t, J=7.32), 082 (3H, t, J=7.61).

EXAMPLE 59(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol) in DMF (10 mL)were added 2-iodopropane (4.9 g, 28.75 mmol) and K₂CO₃ (4 g, 28.75mmol). The mixture was stirred at rt overnight. The mixture was dilutedwith water (20 mL) extracted with EtOAc (3×25 mL), the combined organicphase was washed with brine, dried over Na₂SO₄, concentrated andpurified by prep TLC to give 5-bromo-1-isopropylpyridin-2(1H)-one (380mg, 31%). ¹H NMR (CDCl₃): 1.35 (d, 6H), 5.65-5.75 (m, 1H), 6.48 (d, 1H),7.30 (m, 1H), 7.41 (d, 1H).

Step 2

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(100 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was added5-bromo-1-isopropylpyridin-2(1H)-one (54.2 mg, 0.25 mmol). Thencatalysts of Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol), Cs₂CO₃ (1 mL, 2 M) wereadded. The vessel was sealed with a septum and placed into the microwavecavity. Microwave irradiation of 100 W was used, the temperature beingramped from room temperature to 120° C. Once this temperature wasreached, the reaction mixture was held at this temperature for 30 min.After the mixture cooled to rt, the mixture was filtered. The filtratewas extracted with EtOAc (20 mL×4), the organic layer was washed withbrine, dried over Na₂SO₄ and concentrated to give the crude productwhich was purified by preparative HPLC to give(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(22 mg, 21%). ¹H NMR (CDCl₃): 1.13 (s, 3H), 1.19 (s, 3H), 1.40 (6H),1.53 (d, 3H), 2.18-2.30 (m, 4H), 2.40 (m, 1H), 2.88 (m, 1H), 5.31 (m,1H), 5.70 (m, 1H), 6.73 (d, 1H), 7.02 (d, 2H), 7.15 (d, 2H), 7.27-7.38(m, 5H), 7.43 (d, 1H), 7.50 (d, 1H).

EXAMPLE 60(R)-6-ethyl-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 32 Method 2Steps 3 and 4 using 5-bromo-1-isopropylpyridin-2(1H)-one in Step 4.LC-MS Method 1 t_(R)=1.75 min, m/z=459 (M+1); ¹H NMR (CDCl₃) 7.49, (1H,dd, J=2.34, 9.37 Hz), 7.42 (1H, d, J=2.34 Hz), 7.32-7.24 (5H, m), 7.13(1H, d, J=8.20), 7.04 (1H, d, J=8.49), 6.66 (1H, d, J=9.37), 5.49 (1H,aq q, J=6.44, 9.37), 5.33 (1H, m), 2.96-2.91 (1H, m), 2.39-2.32 (1H, m),2.29-2.17 (2H, m), 2.05-1.85 (m, 4H), 1.41 (6H, dd, J=1.17, 6.73), 1.01(3H, t, J=7.32 Hz), 0.832 (3H, t, J=7.32 Hz).

5-bromo-1-isopropylpyridin-2(1H)-one was prepared from5-bromopyridin-2(1H)-one and isopropyl iodide following a procedureanalogous to that described in Example 59 Step 1.

EXAMPLE 61(S)-3-((S)-1-(4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 59 using 1 5-bromo-3-methylpyridin-2(1H)-one andmethyl iodide in Step 1. LC-MS Method 2 t_(R)=1.197 min, m/z=475.1; ¹HNMR (CDCl₃) 1.04 (s, 3H), 1.11 (s, 3H), 1.46 (d, 3H), 2.18 (m, 5H), 2.21(m, 1H), 2.29-2.40 (m, 1H), 2.80 (m, 1H), 3.41 (s, 3H), 3.56 (s, 3H),5.60 (m, 1H), 6.91 (d, 2H), 7.07 (d, 2H), 7.21-7.40 (m, 7H).

EXAMPLE 62(S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 59, using 5-bromopyridin-2(1H)-one and ethyl iodidein Step 1 and(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-onein Step 2. LC-MS Method 2 t_(R)=1.205 min, m/z=493.2; ¹H NMR (CDCl₃)1.16 (d, 6H), 1.39 (t, 3H), 1.52 (d, 3H), 2.19 (s, 4H), 2.20-2.31 (m,2H), 2.38-2.50 (m, 1H), 2.90 (m, 1H), 4.04 (m, 2H), 5.69 (m, 1H), 6.66(d, 1H), 7.00 (m, 4H), 7.18 (d, 2H), 7.30 (m, 2H), 7.41 (s, 1H), 7.51(d, 1H). Recrystallization from isopropyl acetate following a procedureanalogous to that described for Example 37 in Recrystallization Method Bafforded a crystalline solid with mp 172-173.6° C.

EXAMPLE 63(R)-6-methyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-methyl-6-phenyl-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 32 Method 2Steps 3 and 4 using 4-iodo-1-methylpyridin-2(1H)-one in Step 4. LC-MSMethod 1 t_(R)=1.55 min, m/z=417 (M+1); ¹H NMR (CDCl₃) 7.41 (1H, d,J=7.03 Hz), 7.33 (2H, d, J=8.20 Hz), 7.29-7.19 (5H, m), 7.10 (1H, d,J=8.20), 6.95 (1H, d=1.76), 6.55 (1H, dd, J=2, 7.03 Hz), 5.51 (1H, q,J=6.49, 9.66 Hz), 3.65 (3H, s), 3.00-2.95 (1H, m), 2.44-2.36 (1H, m),2.33-2.15 (2H, m), 2.06-1.86 (2H, m), 1.64 (3H, s), 1.02 (3H, t, J=7.32Hz).

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-methyl-6-phenyl-1,3-oxazinan-2-onewas prepared from 4-chloro-2-phenylbutan-2-ol and(S)-1-(4-bromophenyl)propan-1-amine following a procedure analogous tothat described in Example 71 Step 2.

4-chloro-2-phenylbutan-2-ol was prepared from3-chloro-1-phenylpropan-1-one and methylmagnesium bromide following aprocedure analogous to that described in Preparation 1 Method 1 Step 2.

EXAMPLE 64(S)-3-((S)-1-(4-(1,6-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 4-bromo-1,6-dimethylpyridin-2(1H)-one following a procedureanalogous to that described in Example 6 Step 1. LC-MS Method 2t_(R)=1.173 min, m/z=475.2; ¹H NMR (CDCl₃) 1.10 (s, 3H), 1.16 (s, 3H),1.51 (d, 3H), 2.18 (m, 3H), 2.21 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H),3.54 (s, 3H), 5.66 (m, 1H), 6.21 (s, 1H), 6.60 (s, 1H), 6.97 (m, 2H),7.23-7.34 (m, 7H).

4-bromo-1,6-dimethylpyridin-2(1H)-one was prepared by methylation of4-bromo-6-methylpyridin-2(1H)-one with methyl iodide using K₂CO₃following a procedure analogous to that described in Example 59 Step 1.

EXAMPLE 65(S)-3-((S)-1-(4-(1-ethyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 1-ethyl-4-iodopyridin-2(1H)-one following a procedure analogous tothat described in Example 6 Step 1. LC-MS Method 2 t_(R)=1.228 min,m/z=971.4; ¹H NMR (CDCl₃) 1.10 (s, 3H), 1.14 (s, 3H), 1.36 (m, 3H), 1.53(d, 3H), 2.17 (s, 2H), 2.21-2.32 (m, 2H), 2.32-2.48 (m, 1H), 2.88 (m,1H), 4.00 (m, 2H), 5.68 (m, 1H), 6.39 (d, 1H), 6.78 (s, 1H), 6.99 (d,2H), 7.27-7.38 (m, 8H).

1-ethyl-4-iodopyridin-2(1H)-one was prepared from4-iodopyridin-2(1H)-one and ethyl iodide following a procedure analogousto that described in Example 59 Step 1.

EXAMPLE 66(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 4-iodo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one following aprocedure analogous to that described in Example 6 Step 1. LC-MS Method2 t_(R)=1.871 min, m/z=471.1; ¹H NMR (CDCl₃) 1.11 (s, 3H), 1.17 (s, 3H),1.53 (d, 3H), 2.16-2.33 (m, 4H), 2.35-2.47 (m, 1H), 2.89 (m, 1H),4.58-4.70 (m, 2H), 5.69 (m, 1H), 6.71 (s, 1H), 7.00 (d, 2H), 7.19-7.38(m, 8H). Recrystallization from isopropyl acetate following a procedureanalogous to that described for Example 37 in Recrystallization Method Bafforded a crystalline solid with mp 144-145.5° C.

4-iodo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one was prepared from4-iodopyridin-2(1H)-one and 2,2,2-trifluoroethyltrifluoromethanesulfonate following a procedure analogous to thatdescribed in Example 59 Step 1.

EXAMPLE 67(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 5-bromo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one following aprocedure analogous to that described in Example 6 Step 1. LC-MS Method2 t_(R)=1.323 min, m/z=471.1; ¹H NMR (CDCl₃) 1.13 (s, 3H), 1.19 (s, 3H),1.53 (d, 3H), 2.19-2.30 (m, 4H), 2.40 (m, 1H), 2.89 (m, 1H), 4.67 (m,2H), 5.69 (m, 1H), 6.70 (d, 1H), 7.03 (d, 2H), 7.13 (d, 2H), 7.29-7.38(m, 6H), 7.55 (d, 1H).

5-bromo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one was prepared from5-bromopyridin-2(1H)-one and 2,2,2-trifluoroethyltrifluoromethanesulfonate following a procedure analogous to thatdescribed in Example 59 Step 1.

EXAMPLE 68(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 4-iodo-1-isopropylpyridin-2(1H)-one following a procedure analogousto that described in Example 6 Step 1. LC-MS Method 2 t_(R)=1.846 min,m/z=489.2; ¹H NMR (CDCl₃) 1.10 (s, 3H), 1.24 (s, 3H), 1.39 (d, 6H), 1.52(d, 3H), 2.17-2.31 (m, 4H), 2.35-2.46 (m, 1H), 2.88 (m, 1H), 5.27 (m,1H), 5.69 (m, 1H), 6.49 (d, 1H), 6.88 (s, 1H), 7.00 (d, 2H), 7.29-7.38(m, 7H), 7.40 (d, 1H). Recrystallization from isopropyl acetatefollowing a procedure analogous to that described for Example 37 inRecrystallization Method B afforded a crystalline solid with mp 134-139°C.

4-iodo-1-isopropylpyridin-2(1H)-one was prepared from4-iodopyridin-2(1H)-one and isopropyl iodide following a procedureanalogous to that described in Example 59 Step 1.

EXAMPLE 693-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

The title compound was prepared from3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrileand 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 3 Step 2. LC-MS Method 1 t_(R)=1.45 min,m/z=488; ¹H NMR (CDCl₃) 7.68(dd, 1H), 7.52 (d, 1H), 7.32 (q, 2H), 7.17(d, 2H), 7.06 (t, 2H), 6.97 (d, 2H), 6.91 (d, 1H), 5.66 (q, 1H), 3.72(s, 3H), 2.99 (dt, 1H), 2.48 (dd, 2H), 2.27 (m, 1H), 2.11 (s, 2H), 1.55(d, 3H), 1.44 (s, 3H), 1.34 (s, 3H).

EXAMPLE 70(S)-3-((S)-1-(4-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-1-ethyl-3-methylpyridin-2(1H)-one following a procedureanalogous to that described in Example 6 Step 1. LC-MS Method 2t_(R)=1.314 min, m/z=489; ¹H NMR (CDCl₃) 1.09 (s, 3H), 1.15 (s, 3H),1.35 (t, 3H), 1.50 (d, 3H), 2.15-2.25 (m, 7H), 2.35 (m, 1H), 2.86 (m,1H), 4.03 (m, 2H), 5.66 (q, 1H), 6.96 (d, 2H), 7.13 (d, 2H), 7.25-7.36(m, 7H).

5-Bromo-1-ethyl-3-methylpyridin-2(1H)-one was prepared by alkylation of5-bromo-3-methylpyridin-2(1H)-one with ethyl iodide following aprocedure analogous to that described in Example 59 Step 1.

EXAMPLE 712,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

Method 1

Step 1

A 250 mL flask was charged with anhydrous CeCl₃ (7.1890 g, 29.2 mmol)and THF (55 mL). The mixture was vigorously stirred for 2 h at rt. Thesuspension was then cooled to −78° C. and a solution of2-methylallylmagnesium chloride (0.5 M in THF, 56 mL, 28.0 mmol) wasadded. After stirring for 2 h at −78° C., a solution of3-chloropropiophenone (3.350 g, 19.8 mmol) in THF (30 mL) was added viacannula. The reaction mixture was allowed to slowly warm to 8° C. whilestirring overnight (18 h). The reaction was then quenched with satd aqNaHCO₃, extracted with EtOAc, and dried over Na₂SO₄. After the solventswere evaporated, the crude 1-chloro-5-methyl-3-phenylhex-5-en-3-ol wasdirectly used in the next step without further purification. LC-MSMethod 1 t_(R)=1.91 min, m/z 248, 207 (M−OH)⁺; ¹H NMR (400 MHz, CDCl₃) δ7.39-7.22 (m, 5H), 4.92 (m, 1H), 4.77 (m, 1H), 3.60-3.53 (m, 1H),3.17-3.10 (m, 1H), 2.67 (d, J=13.2 Hz, 1H), 2.55 (d, J=13.2 Hz, 1H),2.41-2.25 (m, 2H), 1.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 144.55,141.72, 128.32, 126.88, 125.07, 116.50, 74.44, 51.46, 46.34, 40.19,24.22.

Step 2

1-chloro-5-methyl-3-phenylhex-5-en-3-ol (1.28 g, 5.7 mmol),(S)-1-(4-bromophenyl)ethanamine (1.37 g, 1.2 equiv), KI (995 mg, 1.05equiv), K₂CO₃ (1.57 g, 2 equiv) were mixed with acetonitrile (15 mL) andheated to reflux (oil bath 96° C.) for overnight. After being cooled tort, the mixture was filtered, concentrated, and purified bychromatography on a 40-g silica gel column, eluted with 0˜8% MeOH inCH₂Cl₂, to afford1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhex-5-en-3-ol (1.33g, 60%).

Step 3

To a solution of1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhex-5-en-3-ol (1.33g, 3.43 mmol) in CH₂Cl₂ (100 mL) was added pyridine (277 μL, 1 equiv)and triethylamine (717 μL, 1.5 equiv). The mixture was cooled to 0° C.Methyl chloroformate (397 μL, 1.5 equiv) was added slowly. After 15 min,the mixture was warmed to rt slowly and stirred for 3 h. The mixture wasthen diluted with ether (200 mL), washed with 5% aq HCl (2×25 mL), satdaq NaHCO₃ (25 mL) and brine (20 mL), and dried over Na₂SO₄. Afterfiltration and concentration, the crude methyl(S)-1-(4-bromophenyl)ethyl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamatewas used for next steps without further purification.

Step 4

The crude methyl(S)-1-(4-bromophenyl)ethyl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamatefrom above procedure was dissolved in dry THF (75 mL), NaH (60% inmineral oil, 274 mg, 2 equiv) was added slowly at rt. After 10 min, themixture was heated to reflux for 2 h. LC-MS found reaction completed.The mixture was cooled to 0° C., quenched with satd aq NH₄Cl (10 mL),diluted with ether (100 mL), washed with 1% aq HCl (25 mL) and brine (15mL), and dried over Na₂SO₄. After filtration and concentration, thecrude product was purified by chromatography on a 40-g silica gelcolumn, eluted with 10-35% EtOAc in hexanes. The second UV active peakwas collected to afford(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(490 mg 34.5% overall yield for Steps 3 and 4).

Step 5

A mixture of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(490 mg, 1.18 mmol), TsCN (257 mg, 1.2 equiv), PhSiH₃ (157 μL, 1.07equiv) and the cobaltN,N′-bis(3,5-di-tert-butylsalicylidene)-1,1,2,2-tetramethylethenediaminecatalyst prepared as described in Preparation 3 (7.5 mg, 0.01 equiv) andethanol (20 mL) was stirred 4 h at rt. LC-MS found the reactioncompleted. The mixture was concentrated and purified by ISCO (40 gcolumn, 25˜80% EtOAc in Hexanes) to afford 267 mg product (51% yield).LC-MS Method 1 t_(R)=1.89 min., m/z 441, 443 (M+1).

Step 6

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(208 mg, 0.47 mmol) in 1,4-dioxane (5 mL) were added6-oxo-1,6-dihydropyridin-3-ylboronic acid (98 mg, 1.5 equiv), 2.0 M aqCs₂CO₃ solution (500 μL), and Pd(dppf)Cl₂ (20 mg, 0.06 equiv). Themixture was degassed and refilled with N₂ gas 3 times, before beingheated to 90° C. (oil bath) for 3 h. LC-MS found the reaction wascomplete. The mixture was cooled to rt, diluted with EtOAc (25 mL), andwashed with water (10 mL). The aqueous layer was extracted with EtOAc(2×10 mL). The combined organic layers were washed with water (10 mL)and brine (8 mL), and dried over Na₂SO₄. After filtration andconcentration, the residue was purified by chromatography (12-g silicagel cartridge, 0˜10% MeOH in CH₂Cl₂, major UV peak) to afford2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile(202 mg, 94%) as a brown oil. LC-MS Method 1 t_(R)=1.34 min, m/z=456(M+1); ¹H NMR (CDCl₃) 8.01 (d, 1H), 7.80 (s, 1H), 7.36 (dt, 6H), 7.19(d, 2H), 6.98 (m, 3H), 5.65 (d, 1H), 2.98 (d, 1H), 2.50 (m, 2H), 2.32(m, 1H), 2.17 (s, 2H), 1.57 (d, 3H), 1.40 (s, 3H), 1.32 (s, 3H).

Method 2

Step 1.3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one

(Methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.38 g) was addedto3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one(2.0 g) dissolved in tetrahydrofuran (30 mL) and toluene (15 mL). Theresulting solution was stirred at room temperature for 0.5 h and at 75°C. for 1 h. After cooling to room temperature, the solution wasconcentrated and ethyl acetate was added to the residue. The resultingmixture was washed with aqueous NaHCO₃ solution and brine and dried(MgSO₄). The title compound was obtained after removal of the solvent.Yield: 1.9 g (quantitative). Mass spectrum (ESI⁺): m/z=414/416 (Br)[M+H]⁺

Step 2.3-{3-[(S)-1-(4-Bromo-phenyl)-ethyl]-2-oxo-(S)-6-phenyl-[1,3]oxazinan-6-yl}-2,2-dimethyl-propionitrile

3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one(0.21 g), p-toluenesulfonyl cyanide (143 mg), tert-BuOOH (5.5 M indecane, 27 μL), and phenylsilane (64 μL) were added in the given orderto a flask charged with a stir bar,(1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis(3,5-di-tert-butylsalicyliden)cobalt(II)(3 mg) and ethanol (15 mL) in argon atmosphere. The resulting solutionwas stirred at room temperature for 3 h and then concentrated underreduced pressure. The residue was purified by chromatography on silicagel (cyclohexane/ethyl acetate 60:40->0:100) to afford the titlecompound as a resin-like solid. Yield: 0.16 g (70% of theory). Massspectrum (ESI⁺): m/z=441/443 (Br) [M+H]⁺

EXAMPLE 72(S)-3-((S)-1-(4-(1-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-1-ethyl-6-methylpyridin-2(1H)-one following a procedureanalogous to that described in Example 6 Step 1. LC-MS Method 2t_(R)=1.211 min, m/z=489.2; ¹H NMR (CDCl₃) 1.10 (s, 3H), 1.17 (s, 3H),1.49 (s, 9H), 1.57 (d, 3H), 2.22 (m, 4H), 2.37 (m, 1H), 2.84 (m, 1H),5.60 (m, 1H), 5.91 (s, 1H), 7.06 (d, 2H), 7.27-7.40 (m, 5H), 7.68 (d,1H), 7.24 (d, 2H), 8.09 (d, 1H), 8.90 (s, 1H).

4-bromo-1-ethyl-6-methylpyridin-2(1H)-one was prepared by alkylation of4-bromo-6-methylpyridin-2(1H)-one with ethyl iodide using K₂CO₃following a procedure analogous to that described in Example 59 Step 1.

EXAMPLE 73(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(1,5,6-trimethyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-1,5,6-trimethylpyridin-2(1H)-one following a procedureanalogous to that described in Example 6 Step 1. LC-MS Method 2t_(R)=1.187 min, m/z=489.2; ¹H NMR (CDCl₃) 1.10 (s, 3H), 1.15 (s, 3H),1.32 (m, 3H), 1.52 (m, 3H), 1.72 (s, 1H), 2.18 (m, 3H), 2.19 (m, 1H),2.42 (m, 4H), 2.86 (m, 1H), 4.12 (m, 2H), 5.66 (m, 1H), 6.16 (s, 1H),6.53 (s, 1H), 6.98 (m, 2H), 7.23-7.34 (m, 7H).

4-bromo-1,5,6-trimethylpyridin-2(1H)-one was prepared by alkylation of4-bromo-5,6-dimethylpyridin-2(1H)-one with methyl iodide using K₂CO₃following a procedure analogous to that described in Example 59 Step 1.4-bromo-5,6-dimethylpyridin-2(1H)-one was prepared following theprocedure described in McElroy, W. T. and DeShong, P. Org. Lett. 2003,5, 4779.

EXAMPLE 743-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile(6 mg, 0.013 mmol) was dissolved in DMF (2.5 mL). Cs₂CO₃ (c.a. 15 mg,excess) and i-PrI (100 μL, excess) were added. The mixture was stirredfor 3 h at rt. LC-MS found the reaction was complete. The mixture waspurified by prep HPLC to afford3-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(1.99 mg, 30%). LC-MS Method 1 t_(R)=2.03 min, m/z=498; ¹H NMR (CDCl₃)8.35 (d, 1H), 7.80 (dd, 1H), 7.37 (m, 5H), 7.22 (d, 2H), 6.92 (d, 2H),6.83(d, 1H), 5.66 (q, 1H), 5.22 (m, 1H), 2.93 (m, 1H), 2.16 (s, 2H),1.55 (d, 3H), 1.46 (s, 3H), 1.40 (d, 6H), 1.33 (s, 3H).

EXAMPLE 753-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

Method 1

2 M aqueous Na₂CO₃ solution (0.23 mL) was added to a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.11 g) and trifluoro-methanesulfonic acid1-cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl ester (74 mg;alternatively, 4-bromo-1-cyclopropyl-1H-pyridin-2-one was used) indimethylformamide (3 mL). The resulting mixture was sparged with argonfor 15 min, before[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)dichloromethane complex (10 mg) was added. The mixture was heated to100° C. and stirred at this temperature overnight. After cooling toambient temperature, water was added and the resulting mixture wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel (CH₂Cl₂/MeOH 99:1->90:10) to afford thetitle compound as a foam-like solid which was crystallized with littleethyl acetate. Yield: 30 mg (27% of theory); Mass spectrum (ESI⁺):m/z=487 [M+H]⁺. The compound (1.3 g) was recrystallized from 30 mL ofisopropyl acetate. The hot solution, while being stirred, was slowlycooled down to room temperature overnight in the oil bath to yield thecrystalline monohydrate. Mp 108-110° C.

The crystalline monohydrate was also obtained by recrystallization of10.6 g of compound of Example 75 from 170 mL of isopropylacetate thathad been saturated with water. The hot solution, while being stirred,was slowly cooled down to room temperature, stirred for 2 hours at roomtemperature and 1 hour in an ice-bath. The solid was filtered by suctionand dried overnight at 50° C. Yield 10.2 g. Mp 112-114° C.

The compound of Example 75 (2.0 g) was also recrystallized from amixture of 30 mL of tert.butyl methylether and 15 mL of isopropanol. Thesolid was filtered by suction, washed with tert.butyl methylether anddried at 45° C. and then at 65° C. overnight. 100 mg of this solid wasstirred in 3 mL of water to first form a resinous material that later onconverts into a white solid. This was stirred for another hour, filteredby suction and dried overnight at room temperature and then at 65° C.for 3 hours in a circulating air drier to yield a crystallinemonohydrate. Mp 102-108° C.

This crystalline form of the monohydrate may be characterized by meansof its characteristic X-ray powder diffraction (XRPD) pattern.

The crystalline form is characterised by an X-ray powder diffractionpattern that comprises peaks at 21.00, 21.72, 23.98 degrees 2Θ (±0.05degrees 2Θ, wherein said X-ray powder diffraction pattern is made usingCuK_(α1) radiation.

In particular said X-ray powder diffraction pattern comprises peaks at14.25, 21.00, 21.72, 23.10, 23.98, 27.04 degrees 2Θ (±0.05 degrees 2Θ,wherein said X-ray powder diffraction pattern is made using CuK_(α1)radiation.

More specifically, the crystalline form is characterised by followinglattice parameters: orthorhombic symmetry, space group P2₁2₁2₁ with thecell parameters, a=8.65(1)Å, b=15.46(2)Å, c=20.35(2)Å, and cellvolume=2720(7)Å³ obtained by indexing of the X-ray powder diagrammeasured at room temperature using CuK_(α1) radiation, which comprisespeaks at degrees 2Θ (±0.05 degrees 2Θ as contained in Table 2.

TABLE 2 Indexed XRPD peaks up to 30° 2Θ including intensities(normalised) of the monohydrate of Example 75 2 Θ d_(hkl) IntensityIndexing 2 Θ_(obs) − 2 Θ_(calc) [°] [Å] I/I_(o) [%] h k l [°] 7.19 12.294 0 1 1 0.011 8.66 10.21 2 0 0 2 −0.027 11.14 7.94 20 1 0 1 0.032 11.407.76 18 0 2 0 −0.046 11.74 7.53 15 1 1 0 0.027 12.50 7.07 28 1 1 1 0.00414.25 6.21 32 0 1 3 0.004 14.59 6.07 24 1 1 2 −0.013 15.38 5.76 7 1 2 00.014 17.58 5.04 29 1 1 3 0.015 17.68 5.01 13 1 2 2 0.003 18.34 4.83 170 1 4 −0.009 19.32 4.59 2 0 3 2 0.029 20.21 4.39 14 1 2 3 0.006 20.514.33 22 1 3 1 −0.012 20.88 4.25 22 0 2 4 −0.011 21.00 4.23 97 2 0 10.015 21.30 4.17 6 2 1 0 −0.017 21.72 4.09 100 2 1 1 −0.041 22.51 3.9518 0 1 5 −0.061 23.10 3.85 57 2 1 2 0.046 23.57 3.77 6 2 2 0 0.016 23.983.71 65 2 2 1 0.013 24.41 3.64 12 2 0 3 0.023 24.86 3.58 6 1 1 5 0.02625.08 3.55 15 2 1 3 0.013 26.68 3.34 7 1 3 4 0.005 26.92 3.31 25 0 1 60.029 27.04 3.29 48 2 2 3 0.028 27.20 3.28 5 2 3 1 −0.057 27.66 3.22 262 1 4 0.005 28.28 3.15 3 1 0 6 0.034 28.52 3.13 2 1 4 3 0.030 28.85 3.095 1 1 6 0.011 29.40 3.04 2 2 2 4 −0.042 30.00 2.98 3 2 3 3 −0.001 30.182.96 3 2 0 5 0.056

The X-ray powder diffraction patterns are recorded, within the scope ofthe present invention, using a STOE-STADI P-diffractometer intransmission mode fitted with a position-sensitive detector (PSD) and aCu-anode as X-ray source and a Germanium monochromator (CuKα1 radiation,λ=1,54056 Å, 40 kV, 40 mA). In the Table 1 above the values “2Θ [°]”denote the angle of diffraction in degrees and the values “d_(hkl), [Å]”denote the specified distances in Å between the lattice planes. Theintensity shown in the FIG. 1 is given in units of cps (counts persecond).

The crystalline form is characterised by an X-ray powder diffractionpattern, made using CuKα1 radiation, which comprises peaks at degrees 2Θ(±0.05 degrees 2Θ) as shown in FIG. 2.

In order to allow for experimental error, the above described 2 Θ valuesshould be considered accurate to ±0.05 degrees 2Θ. That is to say, whenassessing whether a given sample of crystals of the compound A is thecrystalline form I in accordance with the invention, a 2 Θ value whichis experimentally observed for the sample should be consideredidentical.

X-ray Structure Determination of the Monohydrate of Example 75

The monohydrate of Example 75, O₃₁H₃₆N₂O₅, crystallizes in theorthorhombic space group P2₁2₁2₁ with a=8.4940(17)Å, b=15.480(3)Å,c=20.200(4)Å, V=2656.0(9)Å³, Z=4 and d_(calc)=1.257 g/cm³. X-rayintensity data were collected on a Rigaku Saturn944 CCD area detectoremploying Cu—K_(α), radiation (λ=1.54178 Å) at a temperature of 100(1)K.Data were collected by the rotation method. Rotation images wereprocessed using D*trek Pflugrath, J W (1999) Acta Cryst. D55, 1718-1725.A total of 24559 reflections were measured yielding 4381 uniquereflections (R_(int)=0.061).

The structure was solved by direct methods and refined by full-matrixleast squares based on F² (SHELX-97 Sheldrick, G. M. (2008). Acta Cryst.A64, 112-122. All reflections were used during refinement. The weightingscheme used was w=1/[σ²(F_(o) ²)+0.1542P²+1.3034P] where P=(F_(o)²+2F_(c) ²)/3. Non-hydrogen atoms were refined anisotropically andhydrogen atoms were refined using a “riding” model. Refinement convergedto R₁=0.0772 and wR₂=0.2096 for 4204 reflections for which F>4σ(F) andR₁=0.0823, wR₂=0.2234 and GOF=1.092 for all 4381 unique, non-zeroreflections and 356 variables. The maximum Δ/σ in the final cycle ofleast squares was 0.001 and the two most prominent peaks in the finaldifference Fourier were +0.68 and −0.34 e/Å³.

Table 2A lists cell information, data collection parameters, andrefinement data. Final positional and equivalent isotropic thermalparameters are given in Table 2B. Anisotropic thermal parameters are inTable 2C.

The molecule crystallises as a monohydrate. The water molecule lieswithin a cavity lined by polar functional groups of the title compound.The terminal N-cyclopropyl moiety is statically disordered and wasmodelled in three conformations symmetrically rotated around the N30-C33bond.

TABLE 2A Summary of Structure Determination of the Monohydrate ofExample 75 Formula: C₃₀H₃₄N₂O₅ Formula weight: 502.59 Crystal class:orthorhombic Space group: P2₁2₁2₁ (#19) Z 4 Cell constants: a 8.4940(17)Å b 15.480(3) Å c 20.200(4) Å V 2656.0(9) Å³ μ 0.69 cm⁻¹ crystal size,mm 0.2 × 0.2 × 0.2 D_(calc) 1.257 g/cm³ F(000) 1072 Radiation:Cu—K_(α)(λ = 1.54178 Å) hkl collected: −9 ≦ h ≦ 9; −17 ≦ k ≦ 17; −23 ≦ l≦ 23 No. reflections measured: 24599 No. unique reflections: 4381(R_(int) = 0.061) No. observed reflections 4204 (F > 4σ) No. reflectionsused in refinement 4204 No. parameters 356 R indices (F > 4σ) R₁ =0.0772 wR₂ = 0.2096 GOF: 1.092 Final Difference Peaks, e/Å³ +0.68, −0.34

TABLE 2B Refined Positional Parameters for the Monohydrate of Example 75Atom Atomtype X Y Z U_(eq), Å² O6 O 0.2810(3) 0.85690(15) 0.18748(11)0.0286(6) O7 O 0.5346(3) 0.86676(17) 0.16786(14) 0.0350(7) O18 O0.0932(4) 1.00778(17) 0.17024(14) 0.0394(7) H18 H 0.1679 0.9869 0.14810.059 N2 N 0.4438(4) 0.73979(19) 0.20957(16) 0.0296(7) C19 C 0.6042(5)0.7014(2) 0.20666(19) 0.0298(8) H19 H 0.6704 0.7408 0.1790 0.036 O36 O0.5819(5) 0.14643(17) 0.09269(14) 0.0541(10) C4 C 0.1732(5) 0.7407(2)0.25110(18) 0.0294(8) H4A H 0.1922 0.7735 0.2924 0.035 H4B H 0.08080.7028 0.2581 0.035 C32 C 0.5863(5) 0.2991(2) 0.09586(19) 0.0360(9) H32H 0.5663 0.3002 0.1421 0.043 C12 C −0.0284(5) 0.6427(2) 0.0703(2)0.0369(9) H12 H −0.1058 0.5984 0.0698 0.044 C3 C 0.3166(5) 0.6862(2)0.23465(19) 0.0325(9) H3A H 0.3523 0.6555 0.2749 0.039 H3B H 0.28800.6425 0.2010 0.039 C8 C 0.1127(5) 0.7544(2) 0.12992(17) 0.0281(8) C5 C0.1402(4) 0.8032(2) 0.19446(17) 0.0257(8) C25 C 0.5407(5) 0.5339(2)0.0723(2) 0.0366(10) H25 H 0.5012 0.5330 0.0283 0.044 C21 C 0.5986(5)0.6149(2) 0.17143(18) 0.0305(8) C1 C 0.4262(5) 0.8216(2) 0.18703(18)0.0286(8) C26 C 0.5401(5) 0.6099(2) 0.10768(19) 0.0353(9) H26 H 0.49810.6605 0.0877 0.042 C17 C −0.1619(5) 0.9948(3) 0.2117(2) 0.0373(9) H17AH −0.1209 1.0138 0.2546 0.056 H17B H −0.2516 0.9560 0.2186 0.056 H17C H−0.1961 1.0452 0.1861 0.056 C10 C 0.1735(5) 0.7218(3) 0.01594(19)0.0370(10) H10 H 0.2357 0.7327 −0.0222 0.044 C23 C 0.6562(6) 0.4632(2)0.1648(2) 0.0378(10) H23 H 0.6976 0.4126 0.1850 0.045 C20 C 0.6764(5)0.7000(3) 0.27568(19) 0.0353(9) H20A H 0.6852 0.7592 0.2924 0.053 H20B H0.7813 0.6737 0.2736 0.053 H20C H 0.6092 0.6661 0.3054 0.053 N30 N0.6253(8) 0.2210(2) −0.00457(18) 0.0733(16) C11 C 0.0600(5) 0.6587(3)0.0139(2) 0.0379(10) H11 H 0.0424 0.6266 −0.0255 0.046 C31 C 0.5949(7)0.2169(3) 0.0636(2) 0.0455(11) C15 C −0.0319(5) 0.9467(2) 0.17352(19)0.0316(9) C24 C 0.5991(5) 0.4585(2) 0.10070(19) 0.0327(9) C27 C0.6052(6) 0.3760(2) 0.0640(2) 0.0370(10) C16 C −0.0946(5) 0.9249(3)0.10498(19) 0.0374(10) H16A H −0.1370 0.9772 0.0843 0.056 H16B H −0.17810.8816 0.1088 0.056 H16C H −0.0089 0.9019 0.0777 0.056 C13 C −0.0048(5)0.6906(2) 0.12734(18) 0.0315(9) H13 H −0.0687 0.6803 0.1651 0.038 C14 C0.0091(5) 0.8662(2) 0.21457(18) 0.0298(9) H14A H 0.0348 0.8867 0.25970.036 H14B H −0.0887 0.8318 0.2183 0.036 C9 C 0.1989(5) 0.7701(2)0.07326(17) 0.0322(9) H9 H 0.2764 0.8144 0.0733 0.039 C28 C 0.6334(9)0.3748(3) −0.0051(2) 0.0661(18) H28 H 0.6437 0.4274 −0.0290 0.079 C22 C0.6543(5) 0.5402(2) 0.2003(2) 0.0360(10) H22 H 0.6916 0.5413 0.24470.043 C29 C 0.6454(12) 0.2984(3) −0.0368(2) 0.094(3) H29 H 0.6685 0.2980−0.0828 0.112 C33 C 0.6453(15) 0.1402(3) −0.0380(3) 0.105(3) C34 C0.6533(9) 0.1275(4) −0.1038(3) 0.0431(16) C35 C 0.5373(14) 0.0926(7)−0.0556(4) 0.074(3) C36 C 0.7109(14) 0.0797(7) −0.0330(5) 0.085(3) O80 O0.3853(4) −0.0013(2) 0.09418(16) 0.0473(8) H81 H 0.443(5) 0.044(2)0.099(3) 0.046(14) H82 H 0.429(9) −0.040(4) 0.119(4) 0.12(3)

TABLE 2C Refined Thermal Parameters (U's) for the Monohydrate of Example75 Atom U₁₁ U₂₂ U₃₃ U₂₃ U₁₃ U₁₂ O6 0.0281(15) 0.0252(12) 0.0325(13)−0.0002(10) 0.0002(11) −0.0020(10) O7 0.0308(16) 0.0298(13) 0.0443(15)0.0040(11) 0.0000(13) −0.0037(12) O18 0.0381(17) 0.0313(14) 0.0489(17)0.0009(12) −0.0004(13) −0.0007(12) N2 0.0271(18) 0.0280(15) 0.0338(16)0.0012(12) 0.0034(13) −0.0005(13) C19 0.028(2) 0.0268(18) 0.0344(19)−0.0007(14) 0.0022(15) 0.0040(16) O36 0.101(3) 0.0258(13) 0.0356(15)0.0019(11) −0.0057(17) −0.0051(16) C4 0.032(2) 0.0281(17) 0.0286(18)0.0034(15) 0.0021(15) −0.0020(15) C32 0.046(3) 0.0340(19) 0.0281(18)0.0032(15) 0.0033(17) 0.0018(18) C12 0.031(2) 0.0324(19) 0.047(2)−0.0099(17) −0.0052(18) −0.0029(16) C3 0.035(2) 0.0299(18) 0.0326(18)0.0051(15) 0.0048(16) 0.0009(16) C8 0.029(2) 0.0266(17) 0.0282(18)−0.0023(14) −0.0014(15) 0.0000(15) C5 0.025(2) 0.0232(16) 0.0293(18)0.0024(14) 0.0026(14) −0.0041(15) C25 0.048(3) 0.0340(19) 0.0277(18)0.0038(15) −0.0034(18) 0.0021(18) C21 0.030(2) 0.0308(18) 0.0305(19)0.0017(15) 0.0019(16) 0.0033(16) C1 0.029(2) 0.0244(17) 0.0318(18)−0.0017(15) −0.0010(16) −0.0018(16) C26 0.046(3) 0.0314(19) 0.0285(19)0.0038(15) −0.0007(17) 0.0012(18) C17 0.038(2) 0.036(2) 0.038(2)−0.0063(17) −0.0023(18) 0.0096(18) C10 0.044(2) 0.039(2) 0.0286(19)−0.0019(15) 0.0039(17) 0.0074(19) C23 0.048(3) 0.0284(19) 0.036(2)0.0048(16) −0.0088(19) 0.0060(18) C20 0.032(2) 0.038(2) 0.037(2)−0.0034(16) −0.0009(17) −0.0022(17) N30 0.161(5) 0.0313(19) 0.0279(18)0.0022(16) 0.010(3) 0.017(3) C11 0.038(2) 0.039(2) 0.037(2) −0.0091(16)−0.0071(18) 0.0073(18) C31 0.075(3) 0.033(2) 0.028(2) 0.0016(16)−0.004(2) 0.004(2) C15 0.029(2) 0.0300(18) 0.036(2) −0.0021(15)0.0018(16) 0.0008(15) C24 0.035(2) 0.0329(19) 0.0299(18) −0.0030(15)0.0026(16) −0.0009(16) C27 0.049(3) 0.0249(18) 0.037(2) 0.0026(15)0.0045(19) 0.0042(17) C16 0.041(3) 0.040(2) 0.031(2) 0.0006(16)−0.0028(18) 0.0087(19) C13 0.032(2) 0.0318(18) 0.0304(18) −0.0008(15)0.0049(16) 0.0012(16) C14 0.033(2) 0.0298(19) 0.0268(18) −0.0015(14)0.0000(16) −0.0005(16) C9 0.039(2) 0.0307(18) 0.0273(18) −0.0005(15)−0.0018(16) 0.0031(16) C28 0.130(5) 0.031(2) 0.037(2) 0.0065(18)0.024(3) 0.017(3) C22 0.046(3) 0.0293(19) 0.033(2) 0.0008(15)−0.0074(18) 0.0013(17) C29 0.218(9) 0.032(2) 0.030(3) 0.0057(19)0.030(4) 0.018(4) C33 0.235(8) 0.029(3) 0.052(3) −0.005(2) 0.010(4)0.019(4) C34 0.075(5) 0.031(3) 0.024(3) −0.018(2) 0.018(3) −0.018(3) C350.097(6) 0.069(5) 0.057(4) 0.004(4) −0.002(4) −0.015(5) C36 0.091(6)0.085(6) 0.078(6) −0.002(5) 0.007(5) 0.023(5) O80 0.052(2) 0.0401(17)0.0499(18) 0.0081(15) 0.0030(16) −0.0011(15)

To investigate the stability of the monohydrate of Example 75, a slurryexperiment was performed. In this study, a suspension of the monohydrateof Example 75 was suspended in water for up to seven days. After thetreatment, the mixtures were filtered and an x-ray powder diffraction ofthe filtration residue was measured. No polymorphic change was observedfor the monohydrate of Example 75. In contrast, the anhydrous form ofExample 75 did not remain in the anhydrous state during the measurementby XRPD (30 minutes).

Intermediate XX 1-Cyclopropyl-4-(4-methoxy-benzyloxy)-1H-pyridin-2-one

A microwave-suited vessel charged with a stir bar,4-(4-methoxy-benzyloxy)-1H-pyridin-2-one (0.60 g), cyclopropylboronicacid (0.45 g), pyridine (1.50 mL), triethylamine (1.50 mL), and toluene(4 mL) was sparged with argon for 5 min. Then, Cu(OAc)₂ (0.94 g) wasadded and the mixture was stirred in a microwave oven under microwaveirradiation at 140° C. for 45 min. Then, the solvent was evaporated andwater was added. The resultant mixture was extracted with ethyl acetateand the combined organic extracts were washed with water and aqueousNaHCO₃ solution. After drying (MgSO₄) and removing the solvent, theresidue was purified by chromatography on silica gel (CH₂Cl₂/MeOH99:1->95:5) to afford the title compound as a solid. Yield: 0.17 g (25%of theory); Mass spectrum (ESI⁺): m/z=272 [M+H]⁺.

Intermediate XXI 1-Cyclopropyl-4-hydroxy-1H-pyridin-2-one

Trifluoroacetic acid (1 mL) was added to a flask charged with a stir barand 1-cyclopropyl-4-(4-methoxy-benzyloxy)-1H-pyridin-2-one (0.17 g) andchilled in an ice/EtOH bath. The resulting mixture was stirred withcooling for 1.5 h and at ambient temperature for another 4.5 h. Then,the solution was concentrated under reduced pressure and the residue wastriturated with tert-butyl methyl ether and dried to give the titlecompound as a solid. Yield: 0.10 g (quantitative). Mass spectrum (ESI⁺):m/z=152 [M+H]⁺.

Intermediate XXII Trifluoro-methanesulfonic acid1-cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl ester

Trifluoromethanesulfonic anhydride (0.12 mL) was added to a flaskcharged with a stir bar, 1-cyclopropyl-4-hydroxy-1H-pyridin-2-one (0.10g), NEt₃ (0.24 mL), and dichloromethane (8 mL) and chilled in anice/EtOH bath. The resulting mixture was stirred with cooling for 2 hand at ambient temperature for another 2 h. Then, the solution wasdiluted with dichloromethane and washed in succession with water,aqueous NaHCO₃ solution, and water. The organic solution was dried(MgSO₄), the solvent was removed, and the residue was purified bychromatography on silica gel (dichloromethane/methanol 99:1->90:10) toafford the title compound as a resin-like solid. Yield: 0.07 g (36% oftheory). Mass spectrum (ESI⁺): m/z=284 [M+H]⁺.

Intermediate XXIII 4-Bromo-1-cyclopropyl-1H-pyridin-2-one

A flask charged with a stir bar, 4-bromo-1H-pyridin-2-one (1.80 g),cyclopropylboronic acid (2.00 g), Cu(OAc)₂ (2.00 g), 2,2′-bipyridine(1.70 g), Na₂CO₃ (2.47 g), and 1,2-dichloroethane (75 mL) was heated to70° C. and the mixture was stirred at this temperature in air overnight.Then, another portion of cyclopropylboronic acid (0.50 g) and Na₂CO₃(0.55 g) were added and the mixture was further stirred at refluxtemperature for another 4 h. After cooling to ambient temperature,aqueous NH₄Cl solution was added and the resultant mixture was extractedwith dichloromethane. The combined organic extracts were dried (MgSO₄)and the solvent was evaporated. The residue was purified bychromatography on silica gel (cyclohexane/ethyl acetate 50:50->35:65) toafford the title compound as an oil that crystallized on standing.Yield: 0.82 g (37% of theory); Mass spectrum (ESI⁺): m/z=214/216 (Br)[M+H]⁺.

Method 2

Step 1. 4-Iodopyridin-2(1H)-one

A mixture of 2-chloro-4-iodopyridine (4.943 g, 20.6 mmol) and formicacid (88%, 10 mL) was stirred at 105° C. for 21 h. The excess of formicacid was removed in vacuo, and the mixture was quenched with 2 M aqNa₂CO₃, extracted with CH₂Cl₂, dried over Na₂SO₄. After the solvent wasremoved under reduced pressure, the residue was purified bychromatography on silica gel eluted with CH₂Cl₂/MeOH to afford 1.716 g(38%) of 4-iodopyridin-2(1H)-one as a solid. LC-MS Method 1 t_(R)=0.82min, m/z=222 (MH⁺); ¹H NMR (400 MHz, (CD₃)₂SO) δ 7.14 (d, J=6.5 Hz, 1H),6.87 (s, 1H), 6.49 (d, J =7.0 Hz, 1H).

Step 2.(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(2.646 g, 5.52 mmol) in 1,4-dioxane (60 mL) were added4-iodopyridin-2(1H)-one (1.200 g, 5.43 mmol), 2 M Cs₂CO₃ (14.5 mL), andPdCl₂(dppf).CH₂Cl₂ (0.230 g, 0.28 mmol). The mixture was degassed andheated, under a nitrogen atmosphere, at 120° C. for 15 h. The mixturewas diluted with CH₂Cl₂, dried over Na₂SO₄. After the solvents wereevaporated, the residue was purified by chromatography on silica geleluted with MeOH/CH₂Cl₂ to afford 1.717 g (71%) of(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one.LC-MS Method 1 t_(R)=1.23 min, m/z 389, 447 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m,5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H),2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H),1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).

Step 3.(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

A mixture of(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(1.683 g, 3.77 mmol, 1.0 equiv), Cu(OAc)₂ (0.692 g, 3.81 mmol, 1.01equiv), bipyridine (0.599 g, 3.83 mmol, 1.02 equiv), cyclopropylboronicacid (0.681 g, 7.93 mmol, 2.10 equiv) and Na₂CO₃ (0.890 g, 8.40 mmol,2.23 equiv) in dichloroethane (40 mL) was stirred at 70° C. for 22 hunder air. The reaction mixture was quenched with satd aq NH₄Cl, dilutedwith CH₂Cl₂, dried over Na₂SO₄. After the solvent was removed underreduced pressure, the residue was purified by chromatography on silicagel eluted with MeOH/CH₂Cl₂ to afford 1.560 g (85%) of(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one.LC-MS t_(R)=1.41 min in 3 min chromatography, m/z 429, 487 (MH⁺); ¹H NMR(400 MHz, CD₃OD) δ 7.52 (d, J=7.0 Hz, 1H), 7.29-7.18 (m, 7H), 6.92 (d,J=8.2 Hz, 2H), 6.54 (d, J=1.8 Hz, 1H), 6.47 (dd, J=7.3, 1.8 Hz, 1H),5.47 (q, J=7.0 Hz, 1H), 3.27-3.21 (m, 1H), 2.95-2.91 (m, 1H), 2.48-2.33(m, 2H), 2.15-2.08 (m, 1H), 2.07 (s, 2H), 1.42 (d, J=7.0 Hz, 3H), 1.20(s, 3H), 1.05-1.00 (m, 2H), 0.87 (s, 3H), 0.83-0.79 (m, 2H); ¹³C NMR(100 MHz, CD₃OD) δ 166.17, 155.63, 152.88, 144.03, 142.27, 138.90,136.91, 129.71, 128.70, 128.58, 127.67, 126.09, 116.08, 107.10, 85.19,71.49, 55.13, 54.62, 37.44, 33.24, 32.71, 31.86, 30.03, 15.60, 7.27.(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(ca. 1.5 g) and isopropyl acetate (30 mL) was heated in a 120° C. oilbath, affording a homogeneous solution. Heating was discontinued and theresulting solution was slowly stirred while slowly cooling to rt in theoil bath overnight. The solids were filtered and washed with isopropylacetate, dried at room temperature under high vacuum affordingcrystalline solid Mp 91-94° C.

EXAMPLE 763-{(S)-1-[4-(1-Cyclopropylmethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

2 M aqueous Na₂CO₃ solution (0.84 mL) was added to a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.40 g) and 5-bromo-1-cyclopropylmethyl-1H-pyridin-2-one (0.24 g) indimethyl-formamide (4 mL). The resulting mixture was sparged with argonfor 10 min, before[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane complex (34 mg) was added. The mixture was heated to100° C. and stirred at this temperature for 4 h. After cooling toambient temperature, water was added and the resulting mixture wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel (dichloromethane/methanol 99:1->95:5) toafford the title compound that was crystallized with little ethylacetate. Yield: 0.19 g (46% of theory); Mass spectrum (ESI⁺): m/z=501[M+H]⁺.

Intermediate XXIV 5-Bromo-1-cyclopropylmethyl-1H-pyridin-2-one

KO^(t)Bu (0.68 g) was added to a solution of 5-bromo-1H-pyridin-2-one(1.00 g) in tetrahydrofuran (20 mL) at room temperature. After stirringfor 30 min, cyclopropylmethyl bromide (0.77 mL) and dimethylformamide (3mL) were added to the suspension and the resulting mixture was warmed to70° C. After stirring the mixture at 70° C. for 2 h, the reaction wascomplete. The mixture was cooled to room temperature, diluted with ethylacetate (50 mL), and washed with water (2×20 mL) and brine (20 mL).Then, the solution was dried (MgSO₄) and the solvent was removed to givethe title compound as a colorless oil. Yield: 1.18 g (90% of theory).Mass spectrum (ESI⁺): m/z=228/230 (Br) [M+H]⁺

EXAMPLE 77(R)-6-Methoxymethyl-3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous tothat described in Example 76. Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

EXAMPLE 78(R)-6-Methoxymethyl-3-{(S)-1-[4-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand trifluoro-methanesulfonic acid1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl ester following a procedureanalogous to that described in Example 76. Mass spectrum (ESI⁺): m/z=433[M+H]⁺.

EXAMPLE 793-{(S)-1-[4-(5-Fluoro-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-5-fluoro-1-methyl-1H-pyridin-2-one following a procedureanalogous to that described in Example 76. Mass spectrum (ESI⁺): m/z=479[M+H]⁺. The compound that had been obtained as an oil crystallized onstanding. The solid was dried at 80° C. under vacuum. Melting points:120-125° C. with evolution of gas followed by recrystallization andmelting at 183-184° C.

Intermediate XXV 4-Bromo-5-fluoro-1-methyl-1H-pyridin-2-one

Methyl iodide (0.9 mL) was added to a mixture of potassium carbonate(2.34 g) and 4-bromo-5-fluoro-1H-pyridin-2-one (2.50 g) indimethylformamide (25 mL) at room temperature. The mixture was stirredat room temperature overnight and then water was added. The resultingmixture was extracted with ethyl acetate and the combined extracts werewashed with brine and dried (MgSO₄). The solvent was evaporated toafford the crude title compound that was recrystallized from Et₂O.Yield: 1.22 g (45% of theory); Mass spectrum (ESI⁺): m/z=206/208 (Br)[M+H]⁺.

EXAMPLE 80(S)-6-(2-Hydroxy-2-methyl-propyl)-3-((S)-1-{4-[1-(2-hydroxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following aprocedure analogous to that described in Example 75. Mass spectrum(ESI⁺): m/z=519 [M+H]⁺.

Intermediate XXVI 4-Bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one

A mixture of 4-bromo-1H-pyridin-2-one (0.25 g), 2,2-dimethyl-oxirane(0.26 mL), and potassium carbonate (0.40 g) in dimethylformamide (2.5mL) was stirred under microwave irradiation at 120° C. for 30 min. Aftercooling to ambient temperature, the mixture was concentrated andpurified by HPLC on reversed phase (acetonitrile/water) to afford thetitle compound. Yield: 0.34 g (96% of theory); Mass spectrum (ESI⁺):m/z=246/248 (Br) [M+H]⁺.

EXAMPLE 81(S)-6-(2-Hydroxy-2-methyl-propyl)-3-((S)-1-{4-[1-(3-methoxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-1-(3-methoxy-2-methyl-propyl)-1H-pyridin-2-one following aprocedure analogous to that described in Example 75 Method 1. Massspectrum (ESI⁺): m/z=533 [M+H]⁺.

Intermediate XXVII 3-(4-Bromo-2-oxo-2H-pyridin-1-yl)-2-methyl-propionicacid methyl ester

A mixture of 4-bromo-1H-pyridin-2-one (0.50 g), methyl2-bromoisobutyrate (0.45 mL), and potassium carbonate (0.68 g) indimethylformamide (5 mL) was stirred at 60° C. for 3 h. After cooling toambient temperature, water was added and the resulting mixture wasextracted with ethyl acetate. The combined extracts were washed withbrine, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel (cyclohexane/ethyl acetate 70:30->50:50) toafford the title compound. Yield: 0.53 g (67% of theory); Mass spectrum(ESI⁺): m/z=274/276 (Br) [M+H]⁺. Additionally2-(4-bromo-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester wasobtained {Yield: 0.15 g; Mass spectrum (ESI⁺): m/z=274/276 (Br) [M+H]⁺}

Intermediate XXVIII4-Bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one

LiAlH₄ (1 M solution in tetrahydrofuran, 1.16 mL) was added to asolution of 3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2-methyl-propionic acidmethyl ester (0.53 g) in tetrahydrofuran (6 mL) chilled in an ice bath.After stirring the solution with cooling for 2 h, another portion ofLiAlH₄ (1 M in tetrahydrofuran, 0.29 mL) was added. After stirring withcooling for 1 more hour, the reaction was quenched by the addition ofwater. The resulting mixture was extracted with ethyl acetate and thecombined organic extracts were washed with brine and dried (MgSO₄). Thesolvent was evaporated to give the title compound. Yield: 0.37 g (78% oftheory); Mass spectrum (ESI⁺): m/z=246/248 (Br) [M+H]⁺.

Intermediate XXIX

4-Bromo-1-(3-methoxy-2-methyl-propyl)-1H-pyridin-2-one

NaH (60% in mineral oil, 57 mg) was added to a solution of4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one (0.53 g) indimethylformamide (6 mL) chilled in an ice bath. After stirring thesolution with cooling for 0.5 h, methyl iodide (110 μL) was added. Thecooling bath was removed and the solution was stirred at roomtemperature overnight. Then, the solution was concentrated under reducedpressure and the residue was diluted with water. The resulting mixturewas extracted with ethyl acetate and the combined organic extracts werewashed with brine and dried (MgSO₄). The solvent was evaporated and theresidue was purified by HPLC on reversed phase (acetonitrile/water) togive the title compound as an oil. Yield: 70 mg (30% of theory); Massspectrum (ESI⁺): m/z=260/262 (Br) [M+H]⁺.

EXAMPLE 82(S)-6-(2-Hydroxy-2-methyl-propyl)-3-((S)-1-{4-[1-(3-hydroxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following aprocedure analogous to that described in Example 75. Mass spectrum(ESI⁺): m/z=519 [M+H]⁺.

EXAMPLE 83(S)-6-(2-Hydroxy-2-methyl-propyl)-3-(1-{4-[1-(2-methoxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-1-(2-methoxy-2-methyl-propyl)-1H-pyridin-2-one following aprocedure analogous to that described in Example 75 Method 1. Massspectrum (ESI⁺): m/z=533 [M+H]⁺.

Intermediate XXX 4-Bromo-1-(2-methoxy-2-methyl-propyl)-1H-pyridin-2-one

The title compound was prepared from4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one and methyl iodidefollowing a procedure analogous to that described in Intermediate XXIX.Mass spectrum (ESI⁺): m/z=260/262 (Br) [M+H]⁺.

EXAMPLE 846-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

To a solution of(S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (740 mg, 2.5mmol) in THF (25 mL) was added dropwise allylmagnesium bromide (25 mL,25 mmol) under N₂ at −78° C. The reaction mixture was stirred at −78° C.for 2 h, quenched by addition of satd aq NH₄Cl, and extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄, andfiltered. The solvent was removed under vacuo to give1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg,95% yield), which was used directly in the next step.

Step 2

To a solution of1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg,2.366 mmol) and triethylamine (139 mg, 2.366 mmol) in CH₂Cl₂ (20 mL) wasadded triphosgene (348 mg, 1.18 mmol) at 0° C. under N₂, and the mixturewas stirred at rt overnight. The reaction mixture was quenched withwater, and extracted with CH₂Cl₂. The organic layer was washed withbrine, dried over Na₂SO₄, filtered, concentrated, and purified by columnchromatography to give6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one(480 mg, 56% yield),

Step 3

To a solution of6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one(480 mg, 1.315 mmol) in THF (5 mL) was added BH₃.THF (5.3 mL, 5.3 mmol)at 0° C. under N₂. The reaction mixture was stirred for 2 h, andquenched with water, 3 M aq NaOH (1 mL), and H₂O₂ (5 mL). The resultingmixture was stirred for 2 h, extracted with EtOAc, washed with brine,dried over Na₂SO₄, filtered, and concentrated to afford the crudeproduct, which was purified by prep TLC to give3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one.(110 mg, 22% yield). ¹H NMR (CDCl₃): δ0.88 (m, 6H), 1.45 (m, 3H), 1.60(m, 4H), 1.71 (m, 1H), 1.82 (m, 1H), 1.99 (m, 1H), 2.63 (m, 1H), 3.03(m, 1H), 3.59 (m, 2H), 5.68 (m, 1H), 7.13 (d, 2H), 7.40 (d, 2H),

Step 4

To a mixture of3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one.(41 mg, 0.1 mmol) in acetone (10 mL) was added Jones reagent (2.5 M, 1mL) at 0° C. The mixture was stirred at room temperature for 1 h,concentrated, and extracted with EtOAc. The organic layer wasconcentrated to give the crude product3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoicacid (51 mg, 95% yield), which was used for the next step withoutfurther purification.

Step 5

To a solution of3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoicacid (41 mg, 0.1 mmol) in MeOH (10 mL) was added SOCl₂ (5 mL) at 0° C.The reaction mixture was stirred at room temperature for 2 h,concentrated, and purified by preparative TLC to give methyl3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoate(42 mg, 96% yield).

Step 6

To a solution of methyl3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoate(42 mg, 0.1 mmol) in dry THF (5 mL) was added MeMgBr (2.5 mL, 2.5 mmol,1 M in THF) at −78° C. The mixture was stirred at rt for 0.5 h, quenchedwith satd aq NH₄Cl, and extracted with EtOAc. The organic layer wasconcentrated, and to afford crude3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxy-3-methylbutyl)-6-isopropyl-1,3-oxazinan-2-one.

The two isomers could be separated by preparative HPLC.

Isomer 1: (1.1 mg, 12% yield), ¹H NMR (CDCl₃): δ0.91 (m, 6H), 1.25 (m,6H), 1.44 (d, 3H), 1.70 (m, 4H), 1.85 (m, 2H), 2.01 (m, 1H), 2.74 (m,1H), 3.18 (m, 1H), 5.79 (m, 1H), 7.24 (d, 2H), 7.50 (d, 2H),

Isomer 2: (0.9 mg, 10% yield), ¹H NMR (CDCl₃): δ0.89 (m, 6H), 1.15 (s,6H), 1.45 (m, 5H), 1.55 (m, 3H), 1.85 (m, 1H), 1.99 (m, 1H), 2.64 (m,1H), 2.99 (m, 1H), 5.72 (m, 1H), 7.17 (d, 2H), 7.40 (d, 2H),

Step 7

To a solution of compound3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxy-3-methylbutyl)-6-isopropyl-1,3-oxazinan-2-one(105 mg, 0.255 mmol) in DMSO (8 mL) was added compound4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (198.5 mg,0.781 mmol), KOAc (351.6 mg, 3.587 mmol), and Pd(dppf)Cl₂ (21.9 mg,0.027 mmol) under N₂. The reaction mixture was stirred at 90° C. for 3.5h added H₂O, and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over Na₂SO₄, concentrated, andpurified by preparative TLC to give the two isomers of6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Isomer 1 (17 mg, 15%).

Isomer 2 (10.3 mg, 9%).

Step 8

To a solution of compound 4-iodo-1-methylpyridin-2(1H)-one (17 mg, 0.074mmol) in DME (4.6 mL) was added Pd(PPh₃)₄ (6.7 mg, 0.007 mmol) undernitrogen. The mixture was stirred at room temperature for 1 h, and asolution of compound6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (17 mg, 0.037 mmol) in EtOH (2 mL) and satd aq NaHCO₃ (1.5 mL)were added. The mixture was stirred at 100° C. for 2 h, quenched withwater, and extracted with EtOAc. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated to give the compound6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (10.73 mg, 65.8%). LC-MS Method 2 Method 2 t_(R)=1.03 min,m/z=463, 441; ¹H NMR (CD₃OD): δ 0.89 (m, 6H), 1.11 (s, 6H), 1.42 (m,2H), 1.51 (m, 3H), 1.60 (m, 2H), 1.82-2.02 (m, 2H), 2.69 (m, 1H), 3.03(m, 1H), 3.51 (s, 3H), 5.79 (m, 3H), 6.35 (d, 1H), 6.72 (s, 1H), 7.28(d, 1H), 7.39 (d, 2H), 7.49 (m, 2H).

6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 2 was prepared from6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer following a procedure analogous to that described in Step 8immediately above. LC-MS Method 2 Method 2 t_(R)=1.00 min, m/z=463, 441;¹H NMR (CD₃OD): δ 0.89 (m, 6H), 1.18 (m, 6H), 1.43 (m, 1H), 1.51 (m,3H), 1.63 (m, 2H), 1.76 (m, 2H), 1.92 (m, 1H), 2.61 (m, 1H), 3.12 (m,1H), 3.51 (s, 3H), 5.79 (m, 1H), 6.37 (d, 1H), 6.72 (s, 1H), 7.28 (d,1H), 7.35 (d, 2H), 7.51 (m, 2H).

EXAMPLE 85(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazinan-2-one

Step 1

A mixture of 4-iodopyridin-2(1H)-one (0.2425 g, 1.10 mmol, 1.0 equiv),Cu(OAc)₂ (0.2146 g, 1.18 mmol, 1.07 equiv), bipyridine (0.1832 g, 1.17mmol, 1.07 equiv), cyclopropylboronic acid (0.2122 g, 2.47 mmol, 2.25equiv) and Na₂CO₃ (0.2638 g, 2.49 mmol, 2.27 equiv) in dichloroethane(10 mL) was stirred at 70° C. for 18 h. The reaction mixture wasquenched with satd aq NH₄Cl, diluted with CH₂Cl₂, and dried over Na₂SO₄.After the solvent was removed under reduced pressure, the residue waspurified by chromatography on silica gel eluted with hexanes/ethylacetate to afford 0.2309 g (81%) of1-cyclopropyl-4-iodopyridin-2(1H)-one.

Step 2

To a solution of compound 1-cyclopropyl-4-iodopyridin-2(1H)-one (17.60mg, 0.067 mmol) in DME (2.5 mL) was added Pd(PPh₃)₄ (6.12 mg, 0.006mmol) under nitrogen. The mixture was stirred at rt for 1 h. A solutionof compound(S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(15 mg, 0.034 mmol) in EtOH (1 mL) and satd aq NaHCO₃ (1 mL) were added.The mixture was stirred at 100° C. for 2 h, quenched with water andextracted with EtOAc. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated to give the final crude product, whichwas purified by preparative HPLC to afford the compound(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazinan-2-one(6.50 mg, 43%). LC-MS Method 2 t_(R)=1.00 min, m/z=453; ¹H NMR (CD₃OD):δ0.82 (d, 3H), 0.89 (m, 2H), 0.99 (d, 3H), 1.17 (m, 2H), 1.35 (m, 6H),1.58 (d, 3H), 1.62 (m, 2H), 1.85 (m, 1H), 1.96 (d, 1H), 2.09-2.18 (m,2H), 2.68-2.78 (m, 1H), 3.11 (m, 1H), 3.37 (m, 1H), 5.81 (m, 1H), 6.40(d, 2H), 6.78 (s, 1H), 7.31-7.42 (m, 3H), 7.58 (d, 2H).

EXAMPLE 86(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one following a procedureanalogous to that described in Example 20 Step 2. LC-MS Method 2t_(R)=1.08 min, m/z=513, 491; ¹H NMR (CD₃OD) δ 0.95 (s, 3H), 1.24 (s,3H), 1.26 (s, 1H), 1.52 (d, 3H), 2.12 (s, 2H), 2.18 (m, 1H), 2.40-2.53(m, 2H), 3.02 (m, 1H), 3.52 (m, 0.5H), 3.64 (m, 0.5H), 3.83 (t, 1H),4.15 (t, 1H), 5.53 (m, 1H), 6.61 (m, 1H), 7.01 (d, 2H), 7.25-7.40 (m,7H), 7.79 (m, 2H).

5-Bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one was prepared from5-bromopyridin-2(1H)-one and 2-iodoethanol following a procedureanalogous to that described in Example 20 Step 1.

EXAMPLE 87(S)-3-((S)-1-(4-(1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of 2-fluoroethanol (3.2 g, 50 mmol) and triethylamine (5.5g, 55 mmol) in dichloromethane (60 mL) was added dropwise (CF₃SO₂)₂O(15.5 g, 55 mmol) at −78° C. under N₂. The mixture was stirred at 10-20°C. for 1 h, and treated with water (100 mL). The organic layer waswashed with satd aq NaHCO₃ (100 mL) and brine (100 mL), dried, andconcentrated to give 2-fluoroethyl trifluoromethanesulfonate (8 g, yield82%).

Step 2

A solution of 5-bromopyridin-2(1H)-one (100 mg, 0.58 mmol),2-fluoroethyl trifluoromethanesulfonate (1.1 g, 5.8 mmol), and K₂CO₃(800 mg, 5.8 mmol) in DMF (3 mL) was stirred at rt overnight.2-Fluoroethyl trifluoromethanesulfonate (1.1 g, 5.8 mmol) and K₂CO₃ (800mg, 5.8 mmol) were added, and the mixture was treated with ethyl acetate(20 mL) and water (20 mL). The organic layer was washed with water (2×20mL) and brine (20 mL), dried over Na₂SO₄, concentrated, and purified bypreparative, TLC (1:1 petroleum ether/EtOAc) to give two isomers.

5-bromo-1-(2-fluoroethyl)pyridin-2(/H)-one (30 mg, yield 24%). ¹H NMR(CD₃OD): δ 4.25 (t, 1H), 4.32 (t, 1H), 4.62 (t, 1H), 4.74 (t, 1H), 6.52(d, 1H), 7.61 (dd, 1H), 7.85 (s, 1H).

5-bromo-2-(2-fluoroethoxy)pyridine (30 mg, yield 24%). ¹H NMR (CD₃OD):δ4.46 (t, 1H), 4.53 (t, 1H), 4.64 (t, 1H), 4.76 (t, 1H), 6.79 (d, 1H),7.79 (dd, 1H), 8.18 (s, 1H),

Step 3

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(20 mg, 0.041 mmol), 5-bromo-1-(2-fluoroethyl)pyridin-2(1H)-one (9.2 mg,0.041 mmol), and Cs₂CO₃ (2 N, 0.2 mL, 0.41 mmol) in 1,4-dioxane (2 mL)was added Pd(PPh₃)₂Cl₂ (3 mg, 0.0041 mmol) under N₂. The mixture wasrefluxed for 2 h, treated with EtOAc (10 mL) and water (10 mL). Theorganic layer was dried over Na₂SO₄, concentrated, and purified bypreparative HPLC to give(S)-3-((S)-1-(4-(1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(4.20 mg, 20%). LC-MS Method 2 t_(R)=1.01 min, m/z=515, 493; ¹H NMR(CD₃OD): δ 0.97 (s, 3H), 1.28 (s, 3H), 1.56 (d, 3H), 2.18 (s, 2H), 2.22(m, 1H), 2.49 (m, 2H), 3.05 (m, 1H), 4.37 (t, 1H), 4.43 (t, 1H), 4.69(t, 1H), 4.81 (t, 1H), 5.59 (q, 1H), 6.66 (d, 1H), 7.05 (d, 2H), 7.33(m, 7H), 7.82 (m, 2H).

EXAMPLE 88(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 1-cyclopropyl-4-iodopyridin-2(1H)-one following a procedureanalogous to that described in Example 23 Step 9. LC-MS Method 2t_(R)=1.05 min, m/z=505; ¹H NMR (CDCl₃) δ 0.88 (m, 2H), 1.12 (s, 3H),1.15 (s, 1H), 1.17 (s, 1H), 1.21 (s, 3H), 2.18-2.29 (m, 2H), 2.30-2.34(m, 1H), 2.42 (d, 1H), 2.54 (d, 1H), 2.90 (m, 1H), 3.35 (m, 1H), 5.70(m, 1H), 6.32 (m, 1H), 6.68 (m, 1H), 6.98 (m, 1H), 7.09 (d, 2H), 7.18(t, 1H), 7.25-7.36 (m, 4H), 7.50 (t, 1H).

EXAMPLE 89(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of compound 5-bromopyridin-2(1H)-one (348 mg, 2.0 mmol)and K₂CO₃ (830 mg, 6.0 mmol) in DMF (15 mL) was added ethyl bromoacetatedropwise. The mixture was stirred at room temperature for 2 h, filtered,and the filtrate was concentrated in vacuo. The residue was purified byprep TLC (1:1 PE/EtOAc) to afford ethyl2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (300 mg, 57.7%). ¹H NMR CDCl₃:δ 7.41-7.26 (m, 2H), 6.53-6.5 (d, 1H), 4.59 (s, 2H), 4.28-4.21 (q, 2H),1.32-1.23 (q, 3H).

Step 2

To a solution of ethyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (130 mg,0.5 mmol) in anhydrous THF (5 mL,) was added 1 M MeMgBr (5 mL, 5 mmol)dropwise with stirring at −78° C. The reaction mixture was stirred at−78° C. for 1 h, quenched with aq NH₄Cl (5 mL), and extractde with EtOAc(3×10 mL). The combined organic layer was dried and concentrated to givethe crude final product, which was purified by preparative TLC (1:1PE/EtOAc) to afford the5-bromo-1-(2-hydroxy-2-methylpropyl)pyridin-2(1H)-one (65 mg, 52.9%).

Step 3

To a solution of 5-bromo-1-(2-hydroxy-2-methylpropyl)pyridin-2(1H)-one(20 mg, 81.3 mmol) in DME (6 mL) was added Pd(PPh₃)₄ (10 mg) undernitrogen. The mixture was stirred for 1 h at rt, and a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(38.95 mg, 81.3 mmol) in EtOH (2 mL) and satd aq NaHCO₃ (2 mL) wereadded. The resulting mixture was stirred at 100° C. for 2 h, quenchedwith water, and extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated to give the crude product,which was purified by preparative TLC and preparative HPLC to afford(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(6.5 mg, 15.5%). LC-MS Method 2 t_(R)=0.99 min, m/z=519; ¹H NMR (CDCl₃):δ 7.60-7.57 (d, 1H), 7.43 (s, 1H), 7.36-7.26 (m, 5H), 7.15 (d, 2H), 7.01(d, 2H), 6.70 (d, 1H), 2.85 (m, 1H), 5.69-5.66 (m, 1H), 4.13-4.09 (s,2H), 4.05-3.98 (s, 1H), 2.89-2.86 (m, 1H), 2.44-2.36 (m, 1H), 2.28-2.16(m, 5H), 1.58-1.53 (d, 3H), 1.33-1.30 (s, 6H), 1.19 (s, 3H), 1.12 (s,3H).

EXAMPLE 903-((S)-1-{4-[1-(3-Hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

2 M aqueous Na₂CO₃ solution (0.32 mL) was added to a mixture of4-bromo-1-(3-hydroxy-2,2-dimethyl-propyl)-1H-pyridin-2-one (0.13 g) and(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.15 g) in N,N-dimethylformamide (3 mL). The resulting mixture wassparged with argon for 5 min, before[1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium (II)dichloromethane complex (26 mg) was added. The mixture was heated to100° C. and stirred at this temperature for 4 h. After cooling toambient temperature, water was added and the resulting mixture wasextracted with ethyl acetate. The combined organic extracts were washedwith water and brine and dried (MgSO₄). The solvent was evaporated andthe residue was purified by HPLC on reversed phase(methanol/water/NH₄OH) to afford the title compound as a beige solid.Yield: 0.10 g (60% of theory); Mass spectrum (ESI⁺): m/z=533 [M+H]⁺.

3-(4-Bromo-2-oxo-2H-pyridin-1-yl)-2,2-dimethyl-propionic acid methylester

3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to amixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate(0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. Themixture was heated to 60° C. and stirred at this temperature overnight.After stirring at 80° C. for another 8 h, the mixture was cooled to roomtemperature and water was added. The resultant mixture was extractedwith ethyl acetate and the combined organic extracts were washed withbrine and dried (MgSO₄). The solvent was evaporated and the residue waspurified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)to afford the title compound;3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester(0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% oftheory); Mass spectrum (ESI⁺): m/z=288/300 (Br) [M+H]⁺.

4-Bromo-1-(3-hydroxy-2,2-dimethyl-propyl)-1H-pyridin-2-one

Lithium borohydride (25 mg) was added to a solution of3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2,2-dimethyl-propionic acid methylester (0.29 g) in tetrahydrofuran (3 mL) chilled in an ice bath. Thenmethanol (45 μL) was added and the mixture was stirred in the coolingbath for 1 h and at room temperature overnight. The mixture was dilutedwith tetrahydrofuran and MgSO₄ was added. The mixture was filtered andthe filtrate was concentrated. The residue was purified bychromatography on silica gel (cyclohexane/ethyl acetate 1:1) to affordthe title compound as a colorless oil. Yield: 0.13 g (49% of theory);Mass spectrum (ESI⁺): m/z=260/262 (Br) [M+H]⁺.

EXAMPLE 913-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-(tetrahydro-2H-pyran-4-yl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to thosedescribed in Example 23 with the following changes. In Step 1tetrahydro-2H-pyran-4-carboxylic acid and carbonyl diimidazole were usedin place of 2-fluorobenzoyl chloride and in Step91-cyclopropyl-4-iodopyridin-2(1H)-one was used in place of5-bromo-1-methylpyridin-2(1H)-one. Two isomers were isolated.

Isomer 1. LC-MS Method 2 t_(R)=0.95 min, m/z=495.

Isomer 2. LC-MS Method 2 t_(R)=0.93 min, m/z=495.

EXAMPLE 92(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-trideuteromethyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to thosedescribed in Example 48 Method 2 with the following changes. In Step 1trideuteromethyl iodide was used in place of methyl iodide and in Step 2PdCl₂(dppf) was used in place of PdCl₂(PPh₃)₂. LC-MS Method 1 t_(R)=1.30min, m/z=464.

EXAMPLE 933-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(cyclopropylmethyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 23 Steps 2 to 9.2-cyclopropyl-N-methoxy-N-methylacetamide, prepared by CU mediatedcoupling of 2-cyclopropylacetic acid and N,O-dimethylhydroxylamine, wasused in Step 2. The two isomers of3-((1S)-1-(4-bromophenyl)ethyl)-6-(cyclopropylmethyl)-6-(2-methylallyl)-1,3-oxazinan-2-oneprepared in Step 5 were separated by column chromatography. The twoisomers were separately carried forward through Steps 6-9, using1-cyclopropyl-4-iodopyridin-2(1H)-one in Step 9, to afford the twoisomers of the title compound.

Isomer 1: LC-MS Method 2 t_(R)=1.04 min, m/z=465, 447.

Isomer 2: LC-MS Method 2 t_(R)=1.06 min, m/z=465, 447.

EXAMPLE 943-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-neopentyl-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 23 Steps 2 to 9.N-methoxy-N,3,3-trimethylbutanamide, prepared by HATU mediated couplingof 3,3-dimethylbutanoic acid and N,O-dimethylhydroxylamine, was used inStep 2. The two isomers of3-((1S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-neopentyl-1,3-oxazinan-2-oneprepared in Step 5 were separated by column chromatography. The twoisomers were separately carried forward through Steps 6-9, using1-cyclopropyl-4-iodopyridin-2(1H)-one in Step 9, to afford the twoisomers of the title compound.

Isomer 1: LC-MS Method 2 t_(R)=1.09 min, m/z=503, 481, 423.

Isomer 2: LC-MS Method 2 t_(R)=1.16 min, m/z=481.

EXAMPLE 953-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(3,3-difluorocyclobutyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 23 Steps 2 to 9.3,3-difluoro-N-methoxy-N-methylcyclobutanecarboxamide, prepared by CUmediated coupling of 3,3-difluorocyclobutanecarboxylic acid andN,O-dimethylhydroxylamine, was used in Step 2. The two isomers of3-((S)-1-(4-bromophenyl)ethyl)-6-(3,3-difluorocyclobutyl)-6-(2-methylallyl)-1,3-oxazinan-2-oneprepared in Step 5 were separated by column chromatography. The twoisomers were separately carried forward through Steps 6-9, using1-cyclopropyl-4-iodopyridin-2(1H)-one in Step 9, to afford the twoisomers of the title compound.

Isomer 1: LC-MS Method 1 t_(R)=1.08 min, m/z=501.

Isomer 2: LC-MS Method 1 t_(R)=1.07 min, m/z=501.

EXAMPLES 96-98 Intermediate 1(S)-4-Bromo-1-(1-isocyanato-ethyl)-2-methyl-benzene

Step 1: (R)-2-Methyl-propane-2-sulfinic acid[1-(4-bromo-2-methyl-phenyl)-ethylidene]-amide

Titanium(IV) ethoxide (10.7 mL) was added to a solution of1-(4-bromo-2-methyl-phenyl)-ethanone (4.41 g) and(R)-2-methyl-2-propanesulfinamide (2.76 g) in tetrahydrofuran (45 mL).The resulting solution was heated to 65° C. and stirred at thistemperature for 20 h. Then, the solution was cooled to ambienttemperature and another portion of titanium(IV) ethoxide (5.4 mL) and(R)-2-methyl-2-propane-sulfinamide (1.25 g) were added. After stirringthe solution at 65° C. for another 12 h, the solution was cooled toambient temperature and poured into brine. The resulting mixture wasfiltered over Celite and the organic phase of the filtrate wasseparated. The aqueous phase of the filtrate was extracted with ethylacetate and the extracts were combined with the separated organic phase.The combined organic phases were washed with brine and dried (MgSO₄) andthe solvent was evaporated. The residue was chromatographed on silicagel (cyclohexane/ethyl acetate 9:1→1:1) to afford the title compound.Yield: 6.24 g (95% of theory); Mass spectrum (ESI⁺): m/z=316/318 (Br)[M+H]⁺.

Step 2: (R)-2-Methyl-propane-2-sulfinic acid[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-amide

Lithium tri-sec-butylborohydride (1 mol/L in tetrahydrofuran, 59.2 mL)was added to a solution of (R)-2-methyl-propane-2-sulfinic acid[1-(4-bromo-2-methyl-phenyl)-ethylidene]-amide (6.24 g) intetrahydrofuran (50 mL) chilled in an ice bath. The solution was stirredfor 2 h while warming to room temperature in the cooling bath. Thesolution was then cooled again in an ice bath prior to the carefuladdition of water. The resulting mixture was extracted with ethylacetate and the combined extracts were washed with water, saturatedaqueous NaHCO₃ solution, and brine. After drying (MgSO₄) and evaporatingthe solvent, the title compound was obtained that was directly submittedto the next reaction step. Yield: 8.85 g (ca. 75% pure); Mass spectrum(ESI⁻): m/z=318/320 (Br) [M+H]⁺.

Step 3: (S)-1-(4-Bromo-2-methyl-phenyl)-ethylamine

Hydrochloric acid (4 mol/L in 1,4-dioxane, 46 mL) was added to asolution of (R)-2-methyl-propane-2-sulfinic acid[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-amide (crude from Step 2, 8.85g, ca. 75% pure) in ethyl acetate (80 mL) at room temperature. Thesolution was stirred at room temperature for 1 h and then concentrated.The residue was taken up in water and the resulting mixture was washedwith diethyl ether. The aqueous phase was basified using aqueous 1 MNaOH solution and extracted with dichloromethane. The combined extractswere washed with brine, dried (MgSO₄), and concentrated to afford thetitle compound. Yield: 4.04 g (905 of theory); Mass spectrum (ESI⁻):m/z=214/216 (Br) [M+H]⁺.

Step 4: (S)-4-Bromo-1-(1-isocyanato-ethyl)-2-methyl-benzene

Triphosgene (2.24 g) was added at once to a vigorously stirred mixtureof NaHCO₃ (3.65 g) in water (80 mL) and(S)-1-(4-bromo-2-methyl-phenyl)-ethylamine (4.04 g) in dichloromethane(80 mL) chilled in an ice bath. The cooling bath was removed and themixture was stirred at room temperature for another 30 min. Then theorganic phase was separated and dried (MgSO₄) and the solvent wasevaporated to afford the isocyanate as an oil that was directlysubmitted to the next reaction step. Yield: 4.50 g (99% of theory); Massspectrum (ESI⁻): m/z=240/242 (Br) [M−H]⁻.

Intermediate 2 (S)-1-Bromo-4-(1-isocyanato-ethyl)-2-methyl-benzene

Step 1: (R)-2-Methyl-propane-2-sulfinic acid[1-(4-bromo-3-methyl-phenyl)-ethylidene]-amide

The title compound was prepared from1-(4-bromo-3-methyl-phenyl)-ethanone and(R)-2-methyl-2-propanesulfinamide following a procedure analogous tothat described in Step 1 of Intermediate 1. Mass spectrum (ESI⁺):m/z=316/318 (Br) [M+H]⁺.

Step 2: (R)-2-Methyl-propane-2-sulfinic acid[(S)-1-(4-bromo-3-methyl-phenyl)-ethyl]-amide

The title compound was prepared from (R)-2-methyl-propane-2-sulfinicacid [1-(4-bromo-3-methyl-phenyl)ethylidene]-amide following a procedureanalogous to that described in Step 2 of Intermediate 1. LC-MS (Method5): t_(R)=4.04 min; Mass spectrum (ESI⁺): m/z=318/320 (Br) [M+H]⁺.

Step 3: (S)-1-(4-Bromo-3-methyl-phenyl)-ethylamine

The title compound was prepared from (R)-2-methyl-propane-2-sulfinicacid [(S)-1-(4-bromo-3-methyl-phenyl)ethyl]-amide following a procedureanalogous to that described in Step 3 of Intermediate 1. LC-MS (Method4): t_(R)=3.56 min; Mass spectrum (ESI⁺): m/z=214/216 (Br) [M+H]⁺.

Step 4: (S)-1-Bromo-4-(1-isocyanato-ethyl)-2-methyl-benzene

The title compound was prepared from(S)-1-(4-bromo-3-methyl-phenyl)-ethylamine and triphosgene following aprocedure analogous to that described in Step 4 of Intermediate 1. Massspectrum (ESI⁺): m/z=272/274 (Br) [M+H+MeOH]⁺.

Intermediate 3 5-Bromo-2-isocyanatomethyl-1,3-dimethyl-benzene

The title compound was prepared from 4-bromo-2,6-dimethyl-benzylamineand triphosgene following a procedure analogous to that described inStep 4 of Intermediate 1. Mass spectrum (EI): m/z=239/241 (Br) [M]⁺.

Intermediate 4 4-Bromo-1-cyclopropyl-1H-pyridin-2-one

A flask charged with a stir bar, 4-bromo-1H-pyridin-2-one (1.80 g),cyclopropylboronic acid (2.00 g), Cu(O₂CCH₃)₂ (2.00 g), 2,2′-bipyridine(1.70 g), Na₂CO₃ (2.47 g), and 1,2-dichloroethane (75 mL) was heated to70° C. The mixture was stirred at this temperature in air overnight.Then, further portions of cyclopropylboronic acid (0.50 g) and Na₂CO₃(0.55 g) were added and the mixture was stirred at reflux temperaturefor another 4 h. After cooling to ambient temperature, aqueous NH₄Clsolution was added and the resultant mixture was extracted withdichloromethane. The combined organic extracts were dried (MgSO₄) andthe solvent was evaporated. The residue was purified by chromatographyon silica gel (cyclohexane/ethyl acetate 50:5035:65) to afford the titlecompound as an oil that crystallized on standing. Yield: 0.82 g (37% oftheory); Mass spectrum (ESI⁺): m/z=214/216 (Br) [M+H]⁺.

EXAMPLE 963-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-2-methyl-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

Step 1:3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one

Lithium hexamethyldisilazide (1 mol/L in tetrahydrofuran, 18.7 mL) wasadded dropwise (at such a rate that the solution temperature maintainsbelow 25° C.) to a solution of 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol(3.82 g) and (S)-4-bromo-1-(1-isocyanato-ethyl)-2-methyl-benzene (4.49g) in tetrahydrofuran (140 mL) chilled in an ice bath. The solution wasstirred in the cooling bath for 30 min and at room temperature foranother 60 min. Then acetic acid (1.9 mL) in water (40 mL) was slowlyadded to the reaction mixture. The resulting mixture was concentratedunder reduced pressure and the residue was taken up in tert-butyl methylether. The resulting solution was washed with water, dried (MgSO₄), andconcentrated. The residue was submitted to chromatography on silica gel(cyclohexane/ethyl acetate 90:10-40:60) to afford the title compound asa colorless solid. Besides the title compound a diastereomer thereof,3-[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-6-(S)-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one,was isolated as an oil {1.55 g, Mass spectrum (ESI⁺): m/z=428/430 (Br)[M+H]⁺}. Yield: 1.34 g (18% of theory); Mass spectrum (ESI⁺):m/z=428/430 (Br) [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 1.40 (d, J=6.8 Hz,3H), 1.53 (s, 3H), 1.71 (s, 3H), 1.81-190 (m, 1H), 1.98-2.08 (m, 1H),2.43-ca. 2.51 (m, 3H), 2.86-2.94 (m, 1H), 4.58 (hardly resolved m, 1H),4.77 (hardly resolved m, 1H), 5.30 (q, J=6.8 Hz, 1H), 7.15-7.19 (m, 2H),7.24-7.35 (m, 6H). The assignment of the stereogenic centers of thetitle compound is based on the comparison of the ¹H NMR data with thedata of the known analog3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.

Step 2:3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(S)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one

3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazin-an-2-one(1.34 g) dissolved in dichloromethane (15 mL) was added to a solution of3-chloroperoxybenzoic acid (77%, 0.81 g) in dichloromethane (15 mL)cooled to 5° C. The cooling bath was removed and the solution wasstirred at room temperature overnight. Aqueous 10% Na₂S₂O₃ solution (10mL) and aqueous saturated NaHCO₃ solution (25 mL) were added and theresulting mixture was stirred for further 30 min. The organic phase wasseparated and washed with aqueous Na₂S₂O₃ solution combined with aqueoussaturated NaHCO₃ solution, water, and brine. The organic phase was dried(MgSO₄) and concentrated to furnish the title compound. Yield: 1.55 g(ca. 85-90% pure); LC-MS (Method 4): t_(R)=4.28 min; Mass spectrum(ESI⁺): m/z=444/446 (Br) [M+H]⁺.

Step 3:3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

Lithium triethylborohydride (1 mol/L in tetrahydrofuran, 4.2 mL) wasadded to an ice-cold solution of3-[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-(S)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one(1.55 g, ca. 85-90% pure) in tetrahydrofuran (15 mL) at such a rate thatthe solution temperature remained below 10° C. The resulting solutionwas stirred in the cooling bath for one more hour and at roomtemperature for another 2 h. Then, the solution was cooled in an icebath and the reaction was quenched by the careful addition of water (7mL). After the addition of aqueous hydrochloric acid and ethyl acetate(80 ml), the organic phase was separated, washed with brine, and dried(MgSO₄). The solvent was evaporated to afford the title compound. Yield:1.48 g (95% of theory); LC-MS (Method 4): t_(R)=4.00 min; Mass spectrum(ESI⁺): m/z=446/448 (Br) [M+H]⁺.

Step 4:(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

A flask charged with a stir bar, potassium acetate (1.14 g),bis(pinacolato)diboron (1.10 g),3-[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one(1.48 g), and dimethyl sulfoxide (20 mL) was sparged with argon for 10min. Then, [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II)dichloro-methane complex (0.27 g) was added and the mixture was heatedto 90° C. and stirred at this temperature for 2.5 h. After cooling themixture to ambient temperature, water and ethyl acetate were added andthe resulting mixture was filtered over Celite. The aqueous phase of thefiltrate was separated and extracted twice with ethyl acetate. Theorganic extracts and the organic phase of the filtrate were combined andwashed with water and brine and dried (MgSO₄). The solvent wasevaporated and the residue was chromatographed on silica gel(cyclohexane/ethyl acetate 1:1→1:4) to afford the title compound. Yield:1.23 g (75% of theory); Mass spectrum (ESI⁺): m/z=494 [M+H]⁺.

Step 5:3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-2-methyl-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

2 M aqueous Na₂CO₃ solution (0.41 mL) was added to a mixture of4-bromo-1-cyclopropyl-1H-pyridin-2-one (0.11 g) and(S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one(0.20 g) in N,N-dimethylformamide (2 mL). The resulting mixture wassparged with argon for 10 min prior to the addition of[1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II)dichloromethane complex (33 mg). The mixture was heated to 100° C. andstirred at this temperature overnight. After cooling the mixture toambient temperature, water was added and the resulting mixture wasextracted with ethyl acetate. The combined organic extracts were washedwith water and brine and dried (MgSO₄). The solvent was evaporated andthe residue was purified by HPLC on reversed phase(methanol/water/NH₄OH) to afford the title compound. Yield: 0.13 g (64%of theory); LC-MS (Method 5): t_(R)=3.43 min; Mass spectrum (ESI⁺):m/z=501 [M+H]⁺.

EXAMPLE 973-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-3-methyl-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

Step 1:3-[(S)-1-(4-Bromo-3-methyl-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol and(S)-1-bromo-4-(1-isocyanato-ethyl)-2-methyl-benzene following aprocedure analogous to that described in Step 1 of Example 96. Massspectrum (ESI⁺): m/z=428/430 (Br) [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 1.40(d, J=6.9 Hz, 3H), 1.55 (s, 3H), 2.13 (s, 3H) superimposed on 2.07-2.18(m, 2H), 2.42-2.47 (m, 1H), 2.53 (broad s, 2H), 2.92-3.03 (m, 1H), 4.60(hardly resolved m, 1H), 4.77 (hardly resolved m, 1H), 5.33 (q, J=6.9Hz, 1H), 6.62 (dd, J=8.2 Hz, 2.0 Hz, 1H), 6.76 (hardly resolved d, 1H),7.26-7.33 (m, 4H), 7.34-7.40 (m, 2H). The assignment of the stereogeniccenters of the title compound is based on the comparison of the ¹H NMRdata with the data of the known analog3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.

Step 2:3-[(S)-1-(4-Bromo-3-methyl-phenyl)-ethyl]-(S)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-[(S)-1-(4-bromo-3-methyl-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-onefollowing a procedure analogous to that described in Step 2 of Example96. LC-MS (Method 4): t_(R)=4.03 min; Mass spectrum (ESI⁺): m/z=444/446(Br) [M+H]⁺.

Step 3:3-[(S)-1-(4-Bromo-3-methyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-[(S)-1-(4-bromo-3-methyl-phenyl)-ethyl]-(S)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-onefollowing a procedure analogous to that described in Step 3 of Example96. LC-MS (Method 4): t_(R)=4.03 min; Mass spectrum (ESI⁺): m/z=446/448(Br) [M+H]⁺.

Step 4:(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-[(S)-1-(4-bromo-3-methyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-onefollowing a procedure analogous to that described in Step 4 of Example96. Mass spectrum (ESI⁺): m/z=494 [M+H]⁺.

Step 5:3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-3-methyl-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-oneand 4-bromo-1-cyclopropyl-1H-pyridin-2-one following a procedureanalogous to that described in Step 5 of Example 96. LC-MS (Method 5):t_(R)=3.42 min; Mass spectrum (ESI⁺): m/z=501 [M+H]⁺.

EXAMPLE 983-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

Step 1:3-(4-Bromo-2,6-dimethyl-benzyl)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol and5-bromo-2-isocyanatomethyl-1,3-dimethyl-benzene following a procedureanalogous to that described in Step 1 of Example 96. LC-MS (Method 5):t_(R)=4.95 min; Mass spectrum (ESI⁺): m/z=428/430 (Br) [M+H]⁺.

Step 2:3-(4-Bromo-2,6-dimethyl-benzyl)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-(4-bromo-2,6-dimethyl-benzyl)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-onefollowing a procedure analogous to that described in Step 2 of Example96. LC-MS (Method 4): t_(R)=4.05 min; Mass spectrum (ESI⁺): m/z=444/446(Br) [M+H]⁺.

Step 3:3-(4-Bromo-2,6-dimethyl-benzyl)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-(4-bromo-2,6-dimethyl-benzyl)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-onefollowing a procedure analogous to that described in Step 3 of Example96. LC-MS (Method 4): t_(R)=4.05 min; Mass spectrum (ESI⁺): m/z=446/448(Br) [M+H]⁺.

Step 4:3-[2,6-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-(4-bromo-2,6-dimethyl-benzyl)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-onefollowing a procedure analogous to that described in Step 4 of Example96. Mass spectrum (ESI⁺): m/z=494 [M+H]⁺.

Step 5:3-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-oneand 4-bromo-1-cyclopropyl-1H-pyridin-2-one following a procedureanalogous to that described in Step 5 of Example 96. LC-MS (Method 5):t_(R)=3.53 min; Mass spectrum (ESI⁺): m/z=501 [M+H]⁺.

BIOLOGICAL TEST EXAMPLE 1

The inhibition of a microsomal preparation of 11β-HSD1 by compounds ofthe invention was measured essentially as previously described (K.Solly, S. S. Mundt, H. J. Zokian, G. J. Ding, A. Hermanowski-Vosatka, B.Strulovici, and W. Zheng, High-Throughput Screening of11-Beta-Hydroxyseroid Dehydrogenase Type 1 in Scintillation ProximityAssay Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactionswere carried out at rt in 96 well clear flexible PET Microbeta plates(PerkinElmer). The assay begins by dispensing 49 μl of substratesolution (50 mM HEPES, pH 7.4, 100 mM KCl, 5 mM NaCl, 2 mM MgCl₂, 2 mMNADPH and 160 nM [³H]cortisone (1 Ci/mmol)) and mixing in 1 μL of thetest compounds in DMSO previously diluted in half-log increments (8points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 μL ofenzyme solution containing microsomes isolated from CHO cellsoverexpressing human 11β-HSD1 (10-20 μg/ml of total protein) was added,and the plates were incubated for 90 minutes at rt. The reaction wasstopped by adding 50 μl of the SPA beads suspension containing 10 μM18β-glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GEHealthcare) and 3.3 μg/ml of anti-cortisol antibody (East CoastBiologics) in Superblock buffer (Bio-Rad). The plates were shaken for120 minutes at rt, and the SPA signal corresponding to [³H]cortisol wasmeasured on a Microbeta plate reader.

BIOLOGICAL TEST EXAMPLE 2

The inhibition of 11β-HSD1 by compounds of this invention was measuredin whole cells as follows. Cells for the assay were obtained from twosources: fully differentiated human omental adipocytes from Zen-Bio,Inc.; and human omental pre-adipocytes from Lonza Group Ltd.Pre-differentiated omental adipocytes from Zen-Bio Inc. were purchasedin 96-well plates and were used in the assay at least two weeks afterdifferentiation from precursor preadipocytes. Zen-Bio induceddifferentiation of pre-adipocytes by supplementing medium withadipogenic and lipogenic hormones (human insulin, dexamethasone,isobutylmethylxanthine and PPAR-gamma agonist). The cells weremaintained in full adipocyte medium (DMEM/Ham's F-12 (1:1, v/v), HEPESpH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B,supplied by Zen-Bio, Inc.) at 37° C., 5% CO₂.

Pre-adipocytes were purchased from Lonza Group Ltd. and placed inculture in Preadipocyte Growth Medium-2 supplemented with fetal bovineserum, penicillin, and streptomycin (supplied by Lonza) at 37° C., 5%CO₂. Pre-adipocytes were differentiated by the addition of insulin,dexamethasone, indomethacin and isobutyl-methylxanthine (supplied byLonza) to the Preadipocyte Growth Medium-2. Cells were exposed to thedifferentiating factors for 7 days, at which point the cells weredifferentiated and ready for the assay. One day before running theassay, the differentiated omental adipocytes were transferred intoserum- and phenol-red-free medium for overnight incubation. The assaywas performed in a total volume of 200 μL. The cells were pre-incubatedwith serum-free, phenol-red-free medium containing 0.1% (v/v) of DMSOand various concentrations of the test compounds at least 1 h before[³H] cortisone in ethanol (50 Ci/mmol, ARC, Inc.) was added to achieve afinal concentration of cortisone of 100 nM. The cells were incubated for3-4 hrs at 37° C., 5% CO₂. Negative controls were incubated withoutradioactive substrate and received the same amount of [³H] cortisone atthe end of the incubation. Formation of [³H] cortisol was monitored byanalyzing 25 μL of each supernatant in a scintillation proximity assay(SPA). (Solly, K.; Mundt, S. S.; Zokian, H. J.; Ding, G. J.;Hermanowski-Vosatka, A.; Strulovici, B.; Zheng, W. Assay Drug Dev.Technol. 2005, 3, 377-384). Many compounds of the invention showedsignificant activity in this assay.

TABLE OF BIOLOGICAL ASSAY RESULTS Biological Test Example 1 Average %inhibition at Compound IC₅₀ Range^(a) 100 nM EXAMPLE 1 ++ 90.3 EXAMPLE 2++ 89.1 EXAMPLE 3 ++ 95.6 EXAMPLE 4 ++ 95.2 EXAMPLE 5 ++ 95.6 EXAMPLE 6++ 92.6 EXAMPLE 7 ++ 75.9 EXAMPLE 8 ++ 84.5 EXAMPLE 9 ++ 86.2 EXAMPLE 10++ 95.8 EXAMPLE 11 ++ 84.1 EXAMPLE 12 ++ 84.2 EXAMPLE 13 ++ 90.0 EXAMPLE14 ++ 91.0 EXAMPLE 15 ++ 92.9 EXAMPLE 16 ++ 95.6 EXAMPLE 17 Isomer 1 ++54.0 EXAMPLE 17 Isomer 2 # 14.8 EXAMPLE 18 Isomer 1 # 23.7 EXAMPLE 18Isomer 2 ++ 42.6 EXAMPLE 19 ++ 36.5 EXAMPLE 20 ++ 90.9 EXAMPLE 21 Isomer1 ++ 103.5 EXAMPLE 21 Isomer 2 ++ 88.8 EXAMPLE 22 Isomer 1 ++ 82.5EXAMPLE 22 Isomer 2 ++ 88.7 EXAMPLE 23 ++ 88.2 EXAMPLE 24 ++ 87.9EXAMPLE 25 ++ 93.9 EXAMPLE 26 ++ 94.7 EXAMPLE 27 ++ 92.0 EXAMPLE 28Isomer 1 ++ 86.9 EXAMPLE 28 Isomer 2 # 42.9 EXAMPLE 29 ++ 94.1 EXAMPLE30 ++ 96.7 EXAMPLE 31 ++ 90.1 EXAMPLE 32 ++ 96.4 EXAMPLE 33 ++ 95.9EXAMPLE 34 ++ 95.0 EXAMPLE 35 ++ 95.8 EXAMPLE 36 ++ 95.0 EXAMPLE 37 ++96.5 EXAMPLE 38 ++ 74.3 EXAMPLE 39 ++ 99.1 EXAMPLE 40 ++ 95.9 EXAMPLE 41++ 88.7 EXAMPLE 42 ++ 88.4 EXAMPLE 43 ++ 96.6 EXAMPLE 44 ++ 102.0EXAMPLE 45 ++ 97.9 EXAMPLE 46 ++ 94.8 EXAMPLE 47 ++ 100.1 EXAMPLE 48 ++95.0 EXAMPLE 49 ++ 97.4 EXAMPLE 50 ++ 97.1 EXAMPLE 51 ++ 93.4 EXAMPLE 52++ 95.4 EXAMPLE 53 ++ 96.6 EXAMPLE 54 ++ 96.0 EXAMPLE 55 ++ 96.6 EXAMPLE56 ++ 102.8 EXAMPLE 57 ++ 102.2 EXAMPLE 58 ++ 104.7 EXAMPLE 59 ++ 95.9EXAMPLE 60 ++ 94.5 EXAMPLE 61 ++ 96.2 EXAMPLE 62 ++ 96.9 EXAMPLE 63 ++96.2 EXAMPLE 64 ++ 94.9 EXAMPLE 65 ++ 96.1 EXAMPLE 66 ++ 96.0 EXAMPLE 67++ 97.7 EXAMPLE 68 ++ 95.6 EXAMPLE 69 ++ 98.1 EXAMPLE 70 ++ 96.5 EXAMPLE71 ++ 92.2 EXAMPLE 72 ++ 95.6 EXAMPLE 73 ++ 99.2 EXAMPLE 74 ++ 95.0EXAMPLE 75 ++ 87.4 EXAMPLE 84 Isomer 1 # 16.2 EXAMPLE 84 Isomer 2 # 8.0EXAMPLE 85 ++ 68.4 EXAMPLE 86 ++ 87.7 EXAMPLE 87 ++ 107.5 EXAMPLE 88 ++92.4 EXAMPLE 89 ++ 92.6 EXAMPLE 91 Isomer 1 # 22.5 EXAMPLE 91 Isomer 2 #13.8 EXAMPLE 92 ++ 93.7 EXAMPLE 93 Isomer 1 ++ 86.4 EXAMPLE 93 Isomer 2# 18.7 EXAMPLE 94 Isomer 1 # 41.9 EXAMPLE 94 Isomer 2 # 8.2 EXAMPLE 95Isomer 1 # 12.8 EXAMPLE 95 Isomer 2 # 8.0 ^(a)++ means IC₅₀ = <100 nM, +means IC₅₀ = 100-1000 nM, # means IC₅₀ >100 nM, − means IC₅₀ >1000 nM.

BIOLOGICAL TEST EXAMPLE 3

In vitro inhibition of 11β-HSD1 by test compounds was determined withHTRF (Homogeneous Time-Resolved Fluorescence) technology (cisbiointernational, France) detecting cortisol generated from cortisterone byhuman liver microsomes. Briefly, compounds were incubated for 1 hour at37° C. in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH(200 μM) and cortisone (80 nM). Cortisol generated in the reaction wasthen detected with a competitive immunoassay, involving two HTRFconjugates: cortisol linked to XL665 and anti-cortisol antibody labeledwith Europium cryptate. The incubation period for detection reaction wastypically 2 hours. The amount of cortisol was determined by reading thetime-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and665/7.5 nm). The ratio of the two emission signals was then calculated(Em665*10000/Em615). Each assay contained incubations with vehiclecontrols instead of compound as controls for non-inhibited cortisolgeneration (100% CTL; ‘high values’) and incubations with carbenoxoloneas controls for fully inhibited enzyme and cortisol background (0% CTL;‘low values’). Each assay also contained a calibration curve withcortisol to transform the fluorescent data into cortisol concentrations.Percent inhibition of each compound was determined relative to thecarbenoxolone signal.

In following table the 11β-HSD 1 inhibitory activities, determined asdescribed above, wherein 100% indicates no inhibition and a value ofzero or below zero indicates complete inhibition.

TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TEST 3 Average %control inhibition at Example 100 nM 75 −14 76 17 77 59 78 58 79 15 8037 81 11 82 −12 83 54 90 4 96 21 97 47 98 67

BIOLOGICAL TEST EXAMPLE 4

The inhibition of a microsomal preparation of 11β-HSD1 in the presenceof 50% human plasma by compounds of the invention was measured asfollows. Microsomes from CHO cells overexpressing human 11β-HSD1 werediluted into reaction buffer consisting of 25 mM HEPES, pH 7.4, 50 mMKCl, 2.5 mM NaCl, 1 mM MgCl2, and 50% (v/v) human plasma (BioChemed).The assay began by dispensing 49 μl of microsome solution into 96-wellpolypropylene plates and adding 1 μl of the test compounds in DMSO,previously diluted in half-log increments (8 points) starting at 1.0 mM.The reaction was initiated with the addition of 50 μl substrate solutionconsisting of reaction buffer with 2 mM NADPH and 160 nM [³—H]cortisone(1 Ci/mmol). The plates were incubated for 120 minutes at rt, and thereaction was quenched with the addition of 100 μl acetonitrile with 20mM cortisone and 20 mM cortisol. After a ten minute incubation at rt,100 μl of each well was filtered through a MultiScreen HTS, HV filterplate (Millipore) and diluted with 100 μl of reaction buffer withouthuman plasma. [3-H]cortisone and [³—H]cortisol were separated by HPLC ona Zorbax SB-C8 column (4.6×250 mm, Agilent) with an isocratic elution at25% acetonitrile in water with 0.01% trifluoroacetic acid, andradioactivity was quantified with an in-line β-RAM (IN/US Systems,Inc.).

BIOLOGICAL TEST EXAMPLE 5 (Fraction Unbound in Human Plasma)

Plasma protein binding of compounds was determined with EquilibriumDialysis of spiked plasma against compound free dextrane buffer using adialysis membrane with mass cutoff of 5000 Da. Compound concentrationsin plasma and buffer after incubation were measured using HPLC/Massspectrometry.

BIOLOGICAL TEST EXAMPLE 6 (CYP3A4 Inhibition)

The assay was based on a method published by Moody et al. (Xenobiotica1999). The inhibition of cytochrome P450 3A4-isoenzyme catalysedN-demethylation of [N-methyl-14C]-Erythromycin by the test compound wasassayed at 37° C. with human recombinant cytochrome P450 3A4. All assayswere carried out on a robotic system in 96 well plates. The finalincubation volume of 200 μl contained TRIS buffer (0.1 M), MgCl₂ (5 mM),recombinant protein (40 μmol/ml), Erythromycin (50 μM) and the testcompound either at four different concentrations in duplicate (e.g.highest concentration 10-50 μM with subsequent serial 1:5 dilutions) orat a concentration of 10 μM in triplicate. Following a shortpreincubation period, reactions were started with the cofactor (NADPH, 1mM) and stopped by addition of 50 μl aqueous trichloroacetic acid (10%w/v). An aliquot of the incubate was transferred to 96 well solid phaseextraction (SPE) plates and extracted on the cartridge. The resultant[¹⁴C]-formaldehyde/formic acid was not retained on the cartridge and wastherefore separated from the unmetabolized substrate by washing the SPEplates with water. An aliquot of the eluates was transferred into wellplates suitable for liquid scintillation counting. The rate of formationof [¹⁴C]-formaldehyde/formic acid in these incubations was compared to acontrol activity containing no test compound. If the compound was testedat four concentrations, experimental IC₅₀ values were calculated.

BIOLOGICAL TEST EXAMPLE 7 (CYP2C9 Inhibition)

Using a procedure similar to that described in Biological Test Example6, the inhibition of cytochrome P450 2C9-isoenzyme catalysedO-demethylation of [O-methyl-¹⁴C]-Naproxen by the test compound wasassayed at 37° C. with human recombinant cytochrome P450 2C9. Theexperimental IC₅₀ was calculated based on % control at four differentconcentrations.

BIOLOGICAL TEST EXAMPLE 8 (CYP2C19 Inhibition)

Using a procedure similar to that described in Biological Test Example6, the inhibition of cytochrome P450 2C19-isoenzyme catalysedN-demethylation of [N-methyl-¹⁴C]-Diazepam by the test compound wasassayed at 37° C. with human recombinant cytochrome P450 2C19. Theexperimental IC₅₀ was calculated based on % control at four differentconcentrations.

BIOLOGICAL TEST EXAMPLE 9 (CYP2C9 Inhibition)

The inhibition of recombinant CYP2C9 by compounds of the invention wasmeasured using a commercial kit from Invitrogen (cat #2859). Suppliedmicrosomes isolated from insect cells infected with a baculovirusengineered to express human CYP2C9 were diluted to 10 mM in reactionbuffer (100 mM potassium phosphate buffer, pH 8.0) with an NADPHgeneration system (3.33 mM glucose-6-phosphate and 0.4 U/mlglucose-6-phosphate dehydrogenase). 89 μl of this dilution weredispensed to each well of a 96-well, black, polystyrene plate and mixedwith 1 μl of test compound previously diluted in DMSO in half logincrements starting at 3 mM. The assay was initiated by adding 10 μl offluorogenic substrate n-octyloxymethylresorufin (OOMR, 20 μM.) with NADP(100 μM) diluted in reaction buffer. The plate was immediately placed ina Perkin Elmer Fusion plate reader. Reaction progress was monitored bymeasuring fluorescence every two minutes for a total of twenty minutes(530 nM excitation filter/605 nM emission filter).

TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 1, 4 AND 5Biological Biological Test Biological Test Test Example 1 Example 4^(a)Example 5 EXAMPLE IC₅₀ (nM) IC₅₀ (nM) Shift^(b) (%)  1 1.51 2.84 1.88  20.31 15.54 50.94  3 1.59 3.85 2.42  4 1.80 5.60 3.12  5 1.25 3.80 3.04 6 2.36 4.07 1.72  7 35.07 nt  8 18.33 nt  9 4.29 13.12 3.06 10 2.9113.13 4.51 11 5.94 13.51 2.27 12 5.38 31.75 5.90 13 7.22 nt 0.00 14 1.112.88 2.59 15 0.58 2.15 3.70 16 0.90 2.00 2.23 17 Isomer 1 75.98 nt 17Isomer 2 >100.00 nt 18 Isomer 1 >100.00 nt 18 Isomer 2 97.49 nt 19 95.38nt 20 4.28 7.61 1.78 21 Isomer 1 3.89 4.72 1.21 21 Isomer 2 7.21 9.581.33 22 Isomer 1 14.87 75.86 5.10 22 Isomer 2 6.60 20.11 3.05 23 1.994.17 2.10 24 3.70 8.28 2.24 25 2.34 5.44 2.32 26 1.49 8.05 5.39 27 3.498.41 2.41 28 Isomer 1 >100.00 nt 28 Isomer 2 8.89 nt 29 1.39 2.76 1.9930 1.44 3.42 2.37 13.9 31 9.01 25.42 2.82 32 3.58 11.48 3.20 12.3 332.23 3.69 1.66 34 3.19 8.85 2.78 35 2.97 nt 36 2.03 13.62 6.72 37 1.676.44 3.85 14.6 38 5.18 nt 39 1.31 5.10 3.89 40 1.86 7.01 3.77 41 9.2838.06 4.10 42 6.70 53.38 7.97 43 2.23 3.51 1.57 44 1.08 5.60 5.19 451.58 11.85 7.52 46 4.24 16.97 4.00 47 0.96 6.75 7.03 48 1.62 5.54 3.418.7 49 1.03 2.96 2.86 50 0.61 1.97 3.23 51 5.46 7.89 1.45 52 3.24 14.094.35 9.0 53 1.35 4.19 3.10 12.8 54 2.40 7.05 2.94 9.1 55 1.66 7.18 4.317.1 56 1.03 13.19 12.81 57 1.26 12.45 9.92 58 0.87 8.98 10.32 59 1.534.02 2.63 11.7 60 0.75 7.00 9.40 61 1.40 6.99 4.99 62 2.48 11.96 4.82 633.85 102.97 26.73 64 1.64 9.62 5.87 65 0.80 4.64 5.82 66 1.47 6.71 4.585.5 67 2.01 7.29 3.63 68 0.96 4.39 4.59 69 0.72 3.89 5.42 70 1.01 2.632.60 71 0.65 3.96 6.09 72 4.04 8.23 2.04 73 1.99 33.08 16.62 74 1.218.76 7.24 75 1.40 2.80 2.00 15.6 84 Isomer 1 >100 nt 84 Isomer 2 >100 nt85 42.9 nt 86 12.1 24.5 2.0 87 1.4 3.2 2.2 88 1.2 2.9 2.5 89 2.8 4.6 1.791 Isomer 1 >100 nt 91 Isomer 2 >100 nt 92 1.8 6.2 3.4 93 Isomer 1 6.116.3 2.7 93 Isomer 2 >100 94 Isomer 1 >100 94 Isomer 2 >100 95 Isomer1 >100 95 Isomer 2 >100 ^(a)nt means not tested; ^(b)Shift is the IC₅₀determined in Biological Test Example 4 divided by the IC₅₀ determinedin Biological Test Example 1.

TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 6-9 BiologicalBiological Test Biological Test Biological Test Test Example 6 Example 7Example 8 Example 9 CYP3A4, CYP2C9, IC₅₀ CYP2C19, IC₅₀ CYP2C9 EXAMPLEIC₅₀ [μM] [μM] [μM] IC₅₀ [uM]  1  2  3 44 38 >50  4 21 17 22  5 29 37 22 6  7  8  9 10 30.0 11 16.1 12 12.1 13 14 25 18 24 15 16 17 Isomer 1 17Isomer 2 18 Isomer 1 18 Isomer 2 19 20 21 Isomer 1 21 Isomer 2 22 Isomer1 22 Isomer 2 23 >50 >50 44 24 25 33 30 22 26 >50 >50 >50 27 28.1 28.229 7.5 30 >50 >50 27 14.3 31 32 >50 >50 >50 28.7 33 >50 43 17 24.6 34 3536 37 48 43 >50 24.8 38 30.0 39 40 >50 >50 13 27.9 41 42 43 10.5 44 4515.2 46 47 12.1 48 >50 >50 >50 30.0 49 32 29 46 14.8 50 14 11 27 5.1 5152 48 14 8 20.3 53 >50 >50 >50 30.0 54 >50 >50 18 55 >50 29 13 24.3 5657 58 8 3 2 59 >50 >50 37 17.7 60 61 >50 40 18 62 48 >50 38 63 64 >50 3317 65 >50 >50 25 66 18 10 11 67 28 41 34 68 43 47 28 69 23 38 >50 7028 >50 23 71 6 17 24 72 41 35 8 73 74 75 23 19 24 76 10 4 9 77 >50 >5034 78 47 39 40 79 >50 >50 >50 80 >50 >50 38 81 >50 30 12 82 >50 48 2983 >50 14 10 84 Isomer 1 84 Isomer 2 85 86 87 88 >50 28 >50 89 91 Isomer1 91 Isomer 2 92 93 Isomer 1 28.5 93 Isomer 2 94 Isomer 1 94 Isomer 2 95Isomer 1 95 Isomer 2

TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR COMPOUNDS IN BIOLOGICALTESTS 1, 4 AND 5 Biological Biological Biological Test Test TestComparator Example 1 Example 4^(a) Example 5 Compound IC₅₀ (nM) IC₅₀(nM) Shift^(b) (%) 1 0.77 11.97 15.51 2 1.80 14.16 7.88 3 0.75 17.7423.63 0.3 4 1.44 15.24 10.57 5 0.51 18.50 36.10 6 1.48 37.58 25.39 70.99 41.90 42.43 8 0.72 17.85 24.74 9 0.55 11.86 21.45 0.3 10 1.79 53.4929.91 11 0.55 13.40 24.59 0.7 12 1.08 19.54 18.12 0.4 13 0.76 6.32 8.3014 1.30 8.94 6.90 15 0.79 8.94 11.32 ^(a)nt means not tested; ^(b)Shiftis the IC₅₀ determined in Biological Test Example 4 divided by the IC₅₀determined in Biological Test Example 1.

TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR COMPOUNDS IN BIOLOGICALTESTS 6-9 Biological Test Biological Biological Biological Example 6Test Test Test Example CYP3A4, Example 7 Example 8 9 Comparator IC₅₀CYP2C9, CYP2C19, CYP2C9 IC₅₀ Compound [μM] IC₅₀ [μM] IC₅₀ [μM] [uM] 127.0 2 1.4 3 7.4 4.1 5.7 4.9 4 5.1 5 9.9 5.1 8.3 3.7 6 4.4 2.3 8.6 5.0 74.0 8 5.3 2.4 5.6 3.0 9 7.0 3.1 9.3 2.5 10 3.6 11 14.1 6.3 12.5 5.5 124.9 4.6 9.5 2.5 12 4.9 3.9 10.1 13 4.4 5.6 <0.4 7.3 14 19.7 25.9 6.424.6 15 3.1 7.7 <0.4 9.5

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the level of cortisol iseffective in treating a disease state. Thus, the compounds of theinvention can be used in the treatment or prevention of diabetesmellitus (e.g., type II diabetes), obesity, symptoms of metabolicsyndrome, glucose intolerance, hyperglycemica, hypertension,hyperlipidemia, insulin resistance, cardiovascular disease,dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma,Cushing's syndrome, Addison's Disease, visceral fat obesity associatedwith glucocorticoid therapy, depression, anxiety, Alzheimer's disease,dementia, cognitive decline (including age-related cognitive decline),polycystic ovarian syndrome, infertility and hypergonadism. Thecompounds of the invention can be used as therapeutic agents for pseudoCushing's Syndrome associated with alcoholic liver disease. In addition,the compounds modulate the function of B and T cells of the immunesystem and can therefore be used to treat diseases such as tuberculosis,leprosy and psoriasis. They can also be used to promote wound healing,particularly in diabetic patients.

Additional diseases or disorders that are related to 11β-HSD1 activityinclude those selected from the group consisting of lipid disorders,hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, vascular restenosis, pancreatitis, abdominal obesity,neurodegenerative disease, retinopathy, nephropathy, neuropathy,diabetes, coronary heart disease, stroke, peripheral vascular disease,Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X. Afurther disease related to 11β-HSD1 activity is pseudo Cushing'sSyndrome associated with alcoholic liver disease.

A pharmaceutical composition of the invention may, alternatively or inaddition to an 11β-HSD1 inhibitor of the invention, comprise apharmaceutically acceptable salt of a an 11β-HSD1 inhibitor of theinvention and one or more pharmaceutically acceptable carrierstherefore. Alternatively, a pharmaceutical composition of the inventionmay comprise a compound of an 11β-HSD1 inhibitor of the invention or apharmaceutical salt thereof as the only pharmaceutically active agent inthe pharmaceutical composition. The disclosed 11β-HSD1 inhibitors can beused alone or in a combination therapy with one or more additionalagents for the treatment of diabetes, dyslipidemia, cardiovasculardisease, hypertension, obesity, cancer or glaucoma.

The compositions of the invention are 11β-HSD1 inhibitors. Saidcompositions contain compounds having a mean inhibition constant (IC₅₀)against 11β-HSD1 of below about 1,000 nM; preferably below about 100 nM;more preferably below about 50 nM; even more preferably below about 5nM; and most preferably below about 1 nM.

The invention includes a therapeutic method for treating or amelioratingan 11β-HSD1 mediated disorder in a subject in need thereof comprisingadministering to a subject in need thereof an effective amount of an11β-HSD1 inhibitor of the invention, or an enantiomer, diastereomer, orpharmaceutically acceptable salt thereof or composition thereof. As usedherein, “treating” or “treatment” includes both therapeutic andprophylactic treatment. Therapeutic treatment includes reducing thesymptoms associated with a disease or condition and/or increasing thelongevity of a subject with the disease or condition. Prophylactictreatment includes delaying the onset of a disease or condition in asubject at risk of developing the disease or condition or reducing thelikelihood that a subject will then develop the disease or condition ina subject that is at risk for developing the disease or condition.

An embodiment of the invention includes administering an 11β-HSD1inhibiting compound of the invention or composition thereof in acombination therapy with one or more additional agents for the treatmentof diabetes, dyslipidemia, cardiovascular disease, hypertension,obesity, cancer or glaucoma. Agents for the treatment of diabetesinclude insulins, such as Humulin® (Eli Lilly), Lantus® (SanofiAventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gammaagonists, such as Avandia® (rosiglitizone maleate, GSK) and Actos®(pioglitazone hydrochloride, Takeda/Eli Lilly); sulfonylureas, such asAmaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, SanofiAventis), Micronase®/Glynase® (glyburide, Pfizer), andGlucotrol®/Glucotrol XL® and (glipizide, Pfizer); meglitinides, such asPrandin®/NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide,Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such asGlucophase®/Glucophase XR® (metformin HCl, Bristol Myers Squibb) andGlumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs,GLP-1 analogs; DPP-IV inhibitors such as Januvia® (sitagliptin, Merck)and Galvus® (vildagliptin, Novartis); PTB-1 B inhibitors; protein kinaseinhibitors (including AMP-activated protein kinase inhibitors); glucagonantagonists, glycogen synthase kinase-3 beta inhibitors;glucose-6-phoshatase inhibitors; glycogen phosphorylase inhibitors;sodium glucose co-transporter inhibitors, and alpha-glucosidaseinhibitors, such as Precose®/Glucobay®/Prandase®/Glucor® (acarbose,Bayer) and Glyset® (miglitol, Pfizer). Agents for the treatment ofdyslipidemia and cardiovascular disease include statins, fibrates, andezetimbe. Agents for the treatment of hypertension includealpha-blockers, beta-blockers, calcium channel blockers, diuretics,angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutralendopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs),aldosterone synthase inhibitors, aldosterone-receptor antagonists, orendothelin receptor antagonist. Agents for the treatment of obesityinclude orlistat, phentermine, sibutramine and rimonabant.

An embodiment of the invention includes administering an 11β-HSD1inhibiting compound of the invention or composition thereof in acombination therapy with one or more other 11β-HSD1 inhibitors, or withcombination products, such as Avandamet® (metformin HCl androsiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazonemaleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol MyersSquibb); and Glucovance® (glyburide and metformin HCl, Bristol MyersSquibb).

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Additionally, thecompounds of the present invention can be administered intranasally ortransdermally. It will be obvious to those skilled in the art that thefollowing dosage forms may comprise as the active ingredient, eithercompounds or a corresponding pharmaceutically acceptable salt of acompound of the present invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can either besolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier is a finely dividedsolid which is in a mixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from about one to aboutseventy percent of the active ingredient. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcaboxymethylcellulose, a low-melting wax, cocoa butter, and the like.Tablets, powders, cachets, lozenges, fast-melt strips, capsules andpills can be used as solid dosage forms containing the active ingredientsuitable for oral administration.

For preparing suppositories, a low-melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first-melted and the activeingredient is dispersed homogeneously therein, as by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retentionenemas, and emulsions, for example, water or water propylene glycolsolutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral administration can be prepared bydissolving the active ingredient in water and adding suitable colorants,flavors, stabilizing, and thickening agents as desired. Aqueoussuspensions for oral administration can be prepared by dispersing thefinely divided active ingredient in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

The pharmaceutical composition is preferably in unit dosage form. Insuch form, the composition is subdivided into unit doses containingappropriate quantities of the active ingredient. The unit dosage formcan be a packaged preparation, the package containing discretequantities of, for example, tablets, powders, and capsules in vials orampules. Also, the unit dosage form can be a tablet, cachet, capsule, orlozenge itself, or it can be the appropriate amount of any of these inpackaged form.

The quantity of active ingredient in a unit dose preparation may bevaried or adjusted from about 0.1 mg to about 1000.0 mg, preferably fromabout 0.1 mg to about 100 mg. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill inthe art. Also, the pharmaceutical composition may contain, if desired,other compatible therapeutic agents.

In therapeutic treatment or as a method-of-use as an inhibitor of11β-HSD1 or an inhibitor in the production of cortisol in the cell, theactive ingredient is preferably administered orally in a solid dosageform as disclosed above in an amount of about 0.1 mg to about 100 mg perdaily dose where the dose is administered once or more than once daily.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication or patent application were specificallyand individually designated as having been incorporated by reference. Itis understood that the examples and embodiments described herein are forillustrative purposes only, and it will be appreciated that theinvention is susceptible to modification, variation and change withoutdeparting from the proper scope or fair meaning of the appended claims.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

The invention claimed is:
 1. A compound represented by the followingstructural formula:

wherein the compound is a monohydrate and crystalline.
 2. The compoundof claim 1, wherein the compound crystallizes in the monoclinic spacegroup P2₁.
 3. A pharmaceutical composition comprising: i) apharmaceutically acceptable carrier or diluent; and ii) the compound ofclaim
 1. 4. A method of treating a human with a disease or conditionselected from Type II diabetes mellitus, obesity, glucose intolerance,hyperglycemia, hyperlipidemia, insulin resistance, and dyslipidemiacomprising the step of administering to the human with the disease orcondition an effective amount of the compound of claim
 1. 5. The methodof claim 4, wherein the disease is Type II diabetes mellitus.
 6. Acompound represented by the following structural formula:

wherein the compound is a monohydrate and crystalline.
 7. The compoundof claim 6, wherein the compound crystallizes in the orthorhombic spacegroup P2₁2₁2₁.
 8. The compound of claim 6, wherein the compound ischaracterized by X-ray powder diffraction peaks at 2θ angles 8.71, 12.93and 19.16 degrees (±0.05 degrees) using CuKα_(I) radiation.
 9. Thecompound of claim 8, wherein the compound is characterized by X-raypowder diffraction peaks at 2θ angles 8.71, 12.93, 19.16, 19.45 and21.06 degrees (±0.05 degrees) using CuKα_(I) radiation.
 10. Apharmaceutical composition comprising: i) a pharmaceutically acceptablecarrier or diluent; and ii) the compound of claim
 6. 11. A method oftreating a human with a disease or condition selected from Type IIdiabetes mellitus, obesity, glucose intolerance, hyperglycemia,hyperlipidemia, insulin resistance, and dyslipidemia comprising the stepof administering to the human with the disease or condition an effectiveamount of the compound of claim
 6. 12. The method of claim 11, whereinthe disease is Type II diabetes mellitus.
 13. A compound represented bythe following structural formula:

wherein the compound is a monohydrate and crystalline.
 14. The compoundof claim 13, wherein the compound crystallizes in the orthorhombic spacegroup P2₁2₁2₁.
 15. The compound of claim 13, wherein the compound ischaracterized by X-ray powder diffraction peaks at 2θ angles 21.00,21.72, and 23.98 degrees (±0.05 degrees) using CuKα_(I) radiation. 16.The compound of claim 15, wherein the compound is characterized by X-raypowder diffraction peaks at 2θ angles 14.25, 21.00, 21.72, 23.10, 23.98,and 27.04 degrees (±0.05 degrees) using CuKα_(I) radiation.
 17. Apharmaceutical composition comprising: i) a pharmaceutically acceptablecarrier or diluent; and ii) the compound of claim
 13. 18. A method oftreating a human with a disease or condition selected from Type IIdiabetes mellitus, obesity, glucose intolerance, hyperglycemia,hyperlipidemia, insulin resistance, and dyslipidemia comprising the stepof administering to the human with the disease or condition an effectiveamount of the compound of claim
 13. 19. The method of claim 18, whereinthe disease is Type II diabetes mellitus.